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In insulin receptor signaling, the
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activation of insulin receptor triggers
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a dual pathway. Upon activation, this
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insulin receptor mediates two pathways.
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A dual pathway. The first one is the
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metabolic response that is mediated by
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IRS or insulin receptor substrates that
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controls glucose uptake, storage and
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metabolism mediated by PI3 Kakt pathway.
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The second one is a mitogenic response
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that is mediated by SC or IRS. The
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classical RAS map K pathway that
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regulates cell growth proliferation and
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In this video we'll be discussing IR
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mediated metabolic pathway and glute for
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transllocation. A stepwise explanation
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for better understanding then IR
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mediated mitogenic pathway. insulin
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resistance and how this mitogenic
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pathway leads to chronic diseases and
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what are our therapeutic colds and
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promising drug candidates. Let's begin
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with IR metabolic pathway or it's also
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called as PI3 AK pathway. So let's break
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down this entire pathway into simple
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steps for better understanding. Pathway
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is responsible for glucose, lipid and
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protein management, their storage and
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Upon activation of this insulin receptor
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by the binding of insulin
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this IRS insulin receptor substrates
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they are crucial adapter proteins.
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They're family of proteins that acts as
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central hub or docking sides to activate
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downstream pathway that is involved in
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primarily involved in metabolism of
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glucose. This activated insulin receptor
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phosphorates IRS specific tyrosin
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residues on IRS proteins especially IRS1
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This is followed by step one PI3K
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phosphorolated or activated insulin
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receptor substrates recruits and
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which is phosphoetide
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3 kynise in step two causes lipid
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which is a membrane lipid is converted
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to PIP3. So this is mediated by or
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In step three, this PIP3 causes kynise
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recruitment. It pulls two proteins PDK1
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and AKT. Both are protein kinases that
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can phosphorolate many other proteins to
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This is followed by further activation
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of AKT by PDK1. PDK1 phosphorates AKT
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making it fully active to move
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throughout the cell. Now the signal is
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completely running. The negative
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feedback regulator is beaten that is
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actually defosphorulating this PIP3 thus
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inhibiting the signal acts as a break or
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regulate the signal after the metabolic
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task is complete. So AKT is activated.
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It is phosphorolated. AKT is activated.
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Now step five is the most important step
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that is the glucose uptake stimulates
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glute for transllocation to the plasma
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membrane is also associated with
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glycogen synthesis inhibits GSK3 to
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promote sugar storage. Then protein
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synthesis activates MTOR and
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gluconneioenesis inhibition
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phosphorilates fox transcription factors
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to prevent the liver for from making
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excess sugar as the sugar is going to
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enter into the cell. Now let us see in
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detail the step five that is glucose
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uptake by glute for transllocation.
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So step five is a glucose uptake that
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stimulates glute for transllocation to
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the plasma membrane. So this is glucose
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that is present outside the cell.
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Glucose cannot enter the cell. It is not
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permeable. It can enter the cell only
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through this glute for transporters or
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transmembrane channels.
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In muscles and fat cells, majority of
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glute 4 are held in intracellular
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vesicles as you see here. And this is
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called glute for storage vicles. So they
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are locked as vesicles in the cytoplasm.
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If glucose is not present or basil state
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whether where there is no insulin.
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The next step is activated AKT
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phosphorilates a substrate called as
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and this further activates a small GTPSS
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which is a protein that is involved in
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exocytosis of glute for storage
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vesicles. So let us make it more clear.
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So this is the vesicle with glute for
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transporters and activation of the
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signal or aktas 1 160 activation causes
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the movement of this vesicles to the
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plasma membrane and this vesicles fuses
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with the plasma membrane and this glute
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for transporters are embedded into the
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plasma membrane. Now as you see from the
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basil state to the insulin stimulated
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state more glute for transporters are
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loaded into the plasma membrane and that
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actually enhances the glucose uptake
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into the cell. So GSV fuses and embedded
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glute for so there are many glute for
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now in the plasma membrane that enhances
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the ability of the cell to take up
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So this is actually what is happening in
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metabolic pathway. So if this pathway is
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impaired or if there is any problem with
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the glucose will remain outside the
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glucose level in the bloodstream
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which is often called as insulin
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resistance. Hope this is clear. Now let
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us move into the mitogenic pathway.
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Mogenic pathway is often activated at
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high concentration compared to this
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metabolic pathway. So this is the
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mitogenic pathway. This is a classical
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that is responsible for cell
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proliferation, survival and
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differentiation. As we know that insulin
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is a growth hormone also apart from a
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hormone that is involved in metabolism
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of glucose. So upon activation of
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insulin receptor another protein that is
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primarily involved in cro signal that is
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SHC is recruited that is phosphorolated
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phosphorilated SC that acts as an
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adapter recruits another protein which
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that's a step one step two RAS
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activation SOS triggers RAS to exchange
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GDP for GTP that is a classical pathway
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and further pathway downstream. And this
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Ras causes kynes cascade activated Ras
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triggers phosphorilation of Rafmech and
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The classical Raf pathway and signal
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pathway is on. Now finally this
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activated phosphorilated moves into the
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and causes transcription of genes
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that allows or that promotes cell
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division differentiation and survival
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like transcription factors like CIC and
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C force enhances the transcription of
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genes involved in cell division
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migration and also inhibits genes that
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is involved in apoptosis or program cell
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death. So this is the mitogenic signal
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miogenic pathway mediated by insulin
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receptor. Hope you are clear. Now let us
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see how this mitogenic pathway is
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associated with many chronic diseases.
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So this miogenic response is a
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double-edged sword. Suppose this insulin
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receptor has uh some malfunctions or
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downstream pathway is impaired so that
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the signal cannot convey so that this
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pathway this metabolic pathway is
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blocked so that outside the insulin
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concentration rises in the bloodstream.
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This generally activates this mitogenic
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pathway. So this pathway is on that but
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lead to growth and cell division often
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leading to inflammation because of this
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insulin resistance. This is called
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insulin resistance as the glucose cannot
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be metabolized due to the problem with
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the receptor or downstream pathways and
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an unchecked mitogenic pathway is
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happening that lead to many diseases
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like cardiovascular diseases that leads
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to atherogenic dysipidemia
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that means high VLDL low HDL which is a
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good cholesterol and high LDL these high
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VLDL and LDL is atherogenic that can
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cause fatty deposits in the arteries
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leading to major cardiovascular diseases
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or plagues plague deposition.
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Then neurodeeneration is also the reason
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of this activation of the smoggenic
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pathway brain insulin resistance impas
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neuron survival leads to stimulation of
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GSK3 beta which causes
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hyperphosphorilation of tow proteins
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and enhances amoid beta plate
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deposition. the primary reason for
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Alzheimer's. It can of course cause
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cancer. Unchecked MAK signaling and high
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levels of IGF can accelerate the growth
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of neoplasms andiogenesis and metastasis
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in cancers of the breast, colon, liver
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and pancreas. So unchecked mgenic
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pathway activation can lead to many
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chronic diseases associated with insulin
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receptor and insulin receptor mediated
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pathway. So our therapeutic goal is to
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device or a drug that is an agonist that
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is biased towards the metabolic pathway
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or restoring this metabolic pathway
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whereas without interfering with this
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mitogenic pathway or unfounded growth
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signals are avoided.
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There are some promising candidates
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research is going on. First one is
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peptide S596 a synthetic peptide shown
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to selectively activate AKT over uh AKT
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over this ERK pathway. The second one is
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XMET A which is a human monoconal
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antibbody that acts as an alosteric
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activator of the IR improving glycemic
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control with a varable signal profile.
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The research is going on the research is
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going on regarding its further efficacy
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and safety. Hope you understand the
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pathway that is mediated by insulin
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receptor. The two pathways. The first
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one is the metabolic pathway where
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glucose metabolism happens and the
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second one is a mitogenic pathway that
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leads to cell division and growth. Hope
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you are benefited from this video. Take
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care. Stay blessed. Thank you so much.
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You are with biologics4.com.
