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What maintains human blood glucose levels at about 5.5 mM?

The opposing actions of insulin and glucagon


How does eating affect insulin levels?

-Causes a rise in glucose levels, which in turn causes increased secretion of insulin from the beta cells of the endocrine pancreas


True or False: Insulin acts to increase blood glucose levels

FALSE: Insulin acts to DECREASE blood glucose levels

--> Does this by promoting glucose uptake and storage in muscle (fat) and adipose tissue (fat) and glucose storage in liver (glycogen)


What six things do insulin levels affect in humans (that we need to know)?

i) Glucose uptake
ii) Amino acid uptake
iii) Acetyl-Coa --> Fatty acids
iv) Pyruvate --> Glycolysis (gluconeogenesis)
v) Protein synthesis
vi) Glucose --> Glycogen


Is insulin anabolic or catabolic?

Insulin is anabolic
--> Signals building the of macromolecules, cells, and tissues


What kind of receptor is the insulin receptor?

Receptor Tyrosine Kinase (RTK)


Describe the configuration of the insulin receptor

- The Insulin Receptor Is a Monomer of Two Different Proteins Linked by Disulfide Bonds
- Insulin receptor (IR) monomer is comprised of an external α-subunit linked by disulfide bonds to the internal β-subunit
--> Two of these monomers are linked together by disulfide bonds so that IR is already functionally ‘dimeric’ without insulin


What happens to the insulin receptor when insulin binds?

- When insulin binds, it causes a conformational change in the β– subunits that activates their kinase activity and brings the cytoplasmic
domains closer together so they can phosphorylate each other.
- Thus, the two β–subunits transphosphorylate each other, just as occurs with other RTKs


What is Insulin Receptor Substrate (IRS)?

- IRS (insulin receptor substrate) is an adaptor protein, although it is more commonly called a docking protein that is recruited by its PTB domain to the
phosphotyrosines on IR. IRS itself becomes phosphorylated on many tyrosines by the actions of IR. -
- These P-Tyr serve as recognition sites for other
signaling proteins as described for other RTKs


What does the stimulation of the MAPK pathway via insulin receptor do? What part of the insulin receptor stimulates this pathway?

- Grb2 on the insulin receptor stimulates MAPK
- Leads to cell proliferation and Gene transcription


What part of the insulin receptor causes DIRECT stimulation of cell proliferation and gene transcription when it binds to a phosphate group on IRS?



What is The Phoshatidylinositide 3-Kinase (PI3K, PI 3-K)?

• Major kinase in cell growth and survival
• Interacts with many signaling networks,
leading to different biological outcomes
• Pathway altered frequently in cancers
• Promotes cell proliferation and chemo


True or False: PI 3-kinases Are a Family of Protein Kinases That Phosphorylate the 3 position of Phosphoinositols

FALSE: PI 3-kinases Are a Family of LIPID Kinases
That Phosphorylate the 3 position of Phosphoinositols


What is the difference between IP3 and PIP3?

IP3: Stimulates the release of Ca2+ from the ER
PIP3: Recruits proteins to the membrane


Describe the structure of PI 3-K

- PI 3-K has two subunits, p85 and p110
- PI 3-kinase converts the membrane phospholipid 'PIP2' into 'PIP3'


What recognizes PIP3?

PIP3 Is Recognized by PH Domain-Containing
Proteins (ex: Akt / PKB)


What does Akt / PKB do?

- Akt (Protein Kinase B, PKB) recognizes and binds PIP3, which brings it in proximity to PDK1 (another PH domain-containing protein). PDK1 is a serine threonine protein kinase

- PDK1 phosphorylates Akt, activating and releasing it from the membrane; Akt can now phosphorylate its downstream target proteins on ser/thr.
- These targets tend to promote cell growth, cell proliferation, and cell survival


What are the three targets of Akt?

- MDM2


What does mTORC do when phosphorylated by Akt?

Increases cell growth and proliferation


What does MDM2 do when phosphorylated by Akt?

- This is an E3 ubiquitin ligase that targets p53 --> This leads to inappropriate cell survival
---> No cell cycle arrest
---> No DNA repair
---> No apoptosis


What does BAD do when phosphorylated by Akt?

Inhibits Bad to PREVENT apoptosis


What is PTEN?

PTEN is a lipid phosphatase and it dephosphorylates PIP3 on the 3’ position to yield PIP2. PH domain-containing proteins will no longer be recruited to the membrane. PTEN thus is a tumor suppressor of this pathway, and it is mutated in many cancers.


What does Binding of a growth factor or insulin to an RTK activate?

Binding of a growth factor or insulin to an RTK activates PI 3-kinase, a lipid kinase.


What does PIP3 serve as recognition site for?

PIP3 serves as recognition site for PH domain containing kinases such as PDK1 and Akt (PKB).


When does PDK1 phosphorylates and activates Akt?

PDK1 phosphorylates and activates Akt when it is docked at the membrane


What does activated Akt do? What is the ultimate consequence of this?

Activated Akt phosphorylates many proteins, including TOR, MDM2, and BAD. The ultimate consequence is an increase glucose uptake and utilization, increase cell growth, increase cell division, overriding of cell cycle checkpoints, and inhibition apoptosis.


What is PI 3-K signaling negatively regulated by?

PI 3-K signaling is negatively regulated by the lipid phosphatase PTEN, which dephosphorylates PIP3 back to PIP2.


List the pathway from Akt --> mTORC

Akt --> Tsc2 (phosphorylated by Akt)--> Rheb-GTP --> mTORC

--> Tsc2 is a GAP for Rheb (which inactivates Rheb). Akt phosphorylates Tsc2, which inactivates it, allowing Rheb to become activated via the addition of a GTP, which in turn can activate mTORC


What does Rapamycin do in mammals?

Rapamycin inhibits the ser/thr kinase activity of TOR.

--> TOR coordinates cell growth with the environmental conditions. When inactivated by rapamycin, it can no longer do this.


Describe Rapamycin

• Rapamycin is a bacterial peptide discovered in a bacterial sample from the island of Rapa Nui (Easter
Island) in the South Pacific.
• It was originally developed as an antifungal drug, but this was abandoned once it became clear that it had strong immunosuppressant and anti - proliferative actions.
• Mostly used now to prevent rejection in organ transplants, esp. of kidneys