Unit 10 - Integration of Metabolism Flashcards
(31 cards)
What is normal blood glucose level?
Around 5.5 mM, or 100mg/dL
What is the danger of hypoclycemia?
Since your brain uses glucose, lack of glucose means you can go unconcious and die if not helped
What is the danger of hyperglycemia?
Long term effects on cardiovascular health, retina , stroke etc.
What is GLUT1?
Glucose transporter expressed in all tissues
low Km (i.e. low binding affinity)
Highly expressed in tissues with high glycolytic activity
What is GLUT2?
- Has High Km, so will only traport glucose when there is a large amount (high binding affinity, so more likely to bind and hold than release)
- Used as a “sensor” of high glucose
- Expressed in liver and pancreas (esp. ß-cells in pancreas, for insulin secretion)
What is GLUT4?
Insulin-regulated glucose transporter in muscle and adipose tissue. Has a high Vmax (so large capacity for glucose)
What is GLUT 3?
Glucose tranporter with the LOWEST Km, found in the brain and placenta. Low Km allows for continous glucose transport even when glucose levels are low
What are the 3 types of cell-to-cell signalling
Autocrine signalling - release ligand from cell; will affect own function (hence “aut-“)
Paracrine signalling - Ligand acts on cells AROUND it (para-)
Endocrine signalling - Ligand (hormone) affects cells far away via bloodstream; only target cells are activated since they have hormone-specific receptor.
What are the types of hormone receptors?
- Membrane-bound (Insulin, glucagon, epinepherine included) where secondary messengers are required)
- Receptor-channels (hormones affect channel function, ex. open/close)
- Nuclear receptors (hormones cross membrane and bind to nucleus to activate gene expression; ex. steroids)
What is epinepherine? What is its effects?
Hormone secreted by the adrenal gland and bound to adrenergic receptors
Increases heart rate and stimulates glycogen breakdown when bound to ß-adrenergic receptors
Explain the epinepherine signalling cascade.
- ß-adrenergic receptor has epinephrine bind
- G-protein coupled to receptor exchanges GDP to GTP (activates adenylate cyclase)
- Adenylate cyclase turns ATP to cyclic AMP
- Cyclic AMP will activate protein kinase A
- Protein kinase A will be activated to phosphorylate its targets
Where is glucagon and insulin produced and secreted from?
Both come from the Islets of Langerhan located in the pancreas. Insulin comes from ß-cells of the islet, glucagon come from α-cells
How is insulin formed?
- Preproinsulin formed in ER (recall BIOL 200 w/ localization tag)
- Signalling peptide is cleaved to form Proinsulin
- Disulphide bridges form in ER
- Transported to golgi and packaged into vesicles for regulated secretion
- Central part of the proinsulin (C-peptide) cleaved in vesicles, leaving A and B chains connected via disulphide brdiges. This forms mature insulin
- Both Insulin and C chain secreted together
How is the formation of glucaon performed?
Same idea, except slightly more complex. Same polypeptide produced different hormones in different tissues (think: post-translational processing)
How is insulin secreted?
- GLUT2 transports glucose at high blood glucose levels
- Glucose is phosphorylate to G6P by special hexokinase, glucokinase/hexokinase IV which has a high Km and no product inhibition (wherease regular hexokinase has low Km and product inhibition)
- ATP is produced from glucose oxidation
- ATP rise closes potassium channels, which changes the membrane potential
- Rise in membrane potential activates voltage-gated calcium channel, allowing calcium to enter cell
- Calcium flow triggers vesicle fusion, releasing insulin
How is glucagon secreted?
Similar to insulin, except triggered by low glucose and/or neronal signalling. Don’t know exact mechanism though
What is the structure of insulin receptors?
Composed of an extracellular membrane receptor (dimer), transmembrane portion, and an intercellular domain with kinase activity
How does the Insulin receptor work?
- Insulin binds; causes conformation changes and activates kinase activity
- Kinase autophospohorylates itself, incrasing kinase activity
- This induces phosphorylation cascade;
- IR (insulin receptor) activates IR substrate (IRS-1)
- IRS-1 activates PI3K
- PI3K acitvates PDK1
- PDK1 activates AKT
- AKT phoshprylates targets
How does the Glucagon receptor work?
Similar to the epinepherine receptor w/ a G-coupled receptor and Adenylate cyclase
What is the difference between insulin and glucagon’s effects on blood glucose?
Insulin LOWER blood glucose, Glucagon RAISES blood glucose
Insulin:
- Increases uptake
- Increases glcyogen synthesis
- Decreases Glycogen breakdown
- Incrases glycolysis
- Decreases Gluconeogenesis
Glucagon: (literally the reverse)
- Decreases uptake
- Decreases glcyogen synthesis
- Increases Glycogen breakdown
- Decreases glycolysis
- Increases Gluconeogenesis
How does insulin regulate glucose uptake?
When insulin levels rise (ex. after meal), triggers GLUT4 vesicles to fuse with membrane.
- Glucose stored as glycogen in muscles, stored as glycerol and turned into triglycerides in adipose tissue)
*
How is GLUT 4 affected by exercise?
GLUT 4 translocates to membrane due to muscle contraction - ensures delivery of sugars during exercise
Why does the muscle use glycogen stores first?
G6P produce by glycogen breakdown inhibits hexokinase. When glycogen is consumed, hexokinase can take blood glucose and metabolize that
*note that heart muscle usually prefers fats, but prefers sugars during exercise
What are the regulatory components of glycogen metabolism?
Glycogen synthase has 2 states, “ON” (dephosphorylated) and “OFF” (phosphorylated)
Glycogen synthase kinase (GSK) phosphorylates GS (shuts off)
Protein phosphatase 1 (PP1) dephosphortylates GS (turns on)
