Insulin And Glucagon Synthesis And Signaling Flashcards
Classifications of hormones
3 types
1) peptides
- largest class of hormones and range for 3-200 AAs
2) amines
- include thyroid hormones (T3/T4) and catecholamines
- all are derived from tyrosine
3) steroids
- everything from the adrenal cortex, gonads and placenta
Steps of chemical communication
1) signal production and release
2) signal reception
- occurs via signaling molecule binding to the receptor protein
3) signal transmission and amplification
- occurs via intracellular signaling proteins produced from the receptor protein
4) response
- occurs once the intracellular signals initiate their effects
Can be any of the following alterations:
- ion transport
- metabolism
- gene expression
- cell shape or movement
- cell growth and division
Cells of the pancreas islet and their products
Alpha = glucagon
Beta = insulin and amilyn
- amylin = inhibits postprandial glucagon secretion and also inhibits insulin levels from getting to high
Delta = somatostatin
- inhibits insulin, glucagon, gastrin, secretin and GLP 1/2
Gamma = PP-Y
- inhibits pancreatic secretions and intestinal mobility
Epsilon = ghrelin
- stimulates growth hormone release and antagonizes leptin
History of insulin discovery
In 1889 and 1910, dogs were experimented on to remove their pancreas and the effects of it
(Die from glycemic shock)
In 1910 it was deemed that insulin was the molecule secreted to prevent this
Insulin facts
A 51 amino acid molecule combined by alpha and beta polypeptides via disulfide bonds
Production steps
1) Gets produced inside the nuelcus as mRNA and then mRNA moves to cytoplasm of beta cells after the genes coding for insulin produce mRNA inside cell nucleus
2) mRNA is transcribed in cytoplasm and an N-terminal is produced.
3) The N-terminal of the hydrophillic sequence of insulin is put into the RER and begins production of preproinsulin
4) preproinsulin is cleaved at the N-terminal site in the RER lumen in the cisterna space to form proinsulin
5) proinsulin is transported from RER to golgi where it is cleaved to form insulin and C-peptides
6) C-peptides and insulin are packaged in secretory granules and released into bloodstream when signaled
- *C-peptide tests can show indirectly hope much insulin making capacity your beta pancreas cells have**
- type 1 = low C-peptide
- type 2 = high C-peptide
- also can tell if hypoglycemia is caused by excess insulin. Too much synthetic insulin = high insulin but low C-peptide (synthetic doesnt have any)**
Insulin secretion functions
1) use of GLUT 2 receptors bring in glucose, FAs and AAs
- **glucose is the most important signals
2) this induces glycolysis, TCA cycle and oxidative phosphorylation in the B-cells to increase levels ATP
3) high levels of ATP causes inhibit of ATP-dependent K+ channels which reduces the activation energy and leads to membrane depolarization
4) membrane depolarization in B-cells promotes increased intracellular calcium due to voltage-gated calcium channels to occur which causes exocytosis of the insulin and c-peptide vesicles
How do sulfonylurea drugs work?
They block ATP-dependent K+channels regardless of ATP/ADP ratio
This forces the B-cells to induce insulin release
Insulin signaling steps
1) insulin binds to its receptor tyrosine kinase Beta-subunit
2) tyrosine residues of the B-subunits are auto phosphorylated
3) activated receptor tyrosine kinase goes around and phosphorylates other intracellular proteins including insulin receptor substrates (IRS)
4) phosphorylated IRS promotes activation of protein kinases and phosphatase which leads to the metabolic effects of insulin
Metabolic effects of insulin
Activates:
- glucose uptake
- glycogen synthesis
- protein synthesis
- fat synthesis
Inhibits:
- Gluconeogenesis
- glycogenolysis
- lipolysis
glycogen does the exact opposite effects
these are all direct effects of insulin
Mitogenic effects of insulin
Occurs via the RAS/RAF and MAPK/ERK pathways to upregulate other enzyme production
These are non-metabolic effects and are indirect effects of insulin
Insulin effect on glucose uptake
Works on skeletal muscle and adipocytes
1) binds to its tyrosine kinase receptor and activates PI3K and PDK1
2) PI3K and PDK1 phosphorylates and activates PKB/AKT which activate both of these molecules
3) active PKB/AKT induces GLUT4 receptor vesicles to go to the cell surface and insert GLUT 4 receptors
- this protein also goes and induces glucose oxidation/glycogen synthesis/protein and fat synthesis (these effects occur in liver thou)
4) GLUT 4 receptors allow glucose to enter cells down their gradient (facilitated diffusion)
Glucagon production
Produced in the alpha cells from the gene secretin which makes proglucagon.
- enzyme prohormone convertase (PC) converts prohormone into glucagon
The pancreatic alpha cells only secrete this during low blood glucose level signal via the ANS
- also catecholamines and amino acid-rich meals can do it, but hypoglycemia is by far the most important signal
the gene also produces GRPP, GLP-1/2 and IP1/2 peptides
Glucagon signaling pathway
Uses Gs protein system That only activates when glucagon binds to its receptor
- when cAMP-dependent PKA is produced, it cleaves catalytic subunits from regulatory subunits inside target cells to induce actions
The actions are to phosphorylate proteins which induces intracellular effects
Metabolic effects:
1) activates
- glycogenolysis
- gluconeogenesis
- ketogenesis
- FA oxidation
2) inhbits
- glycogenesis
- FA synthesis
