Insulin Signal Transduction Flashcards
What do receptors binding hormone trigger in the target cell?
Intracellular signalling events
What do the signalling events in the cell do?
Control target cell responses
What is the only source of insulin in the body?
Beta pancreatic cells
Why is the insulin gene expressed in beta pancreatic cells and not in otherss?
Gene in open state in beta pancreatic cells, whereas in other cells gene in closed state
What controls whether the insulin gene is in an open or closed state?
Different patterns of histone modification
Other than histone modification, what else controls insulin expression in beta pancreatic cells?
Transcription factors bind to promoter and enhancer elements (= key DNA elements) upstream to transcription start site > regulate access of RNA polymerase II to insulin gene
What is the post-translational processing of insulin?
Preproinsulin translated > signal sequence cleaved > proinsulin > C peptide cleaved > insulin
Why is the beta pancreatic cell at risk from stress events associated with high protein synthesis and release?
Because of high secretory load
What is glucagon-like peptide-1 (GLP-1)?
Endogenous regulator released from gut cells in response to glucose and other nutrients in lumen
What does GLP-1 do?
Releases insulin in Ca-independent way via amplifying cAMP production
What are sulphonyl ureas?
Exogenous drugs
What do sulphonyl ureas do?
Close ATP-gated K channels in beta cells in glucose independent way
Other than glucose, what else affects insulin production?
Circadian rhythm
How many peptides make up insulin?
51
What is the structure of active insulin?
2 chains: A and B, with inter- and intra-chain disulfide bonds
Why can insulin from different species be used to appropriately signal in diabetic human patients?
Sequence and structure highly conserved across species
Why can’t insulin be administered orally?
Because proteolytically digested in gut
What is the structure of the insulin receptor?
2 extracellular alpha chains
2 transmembrane beta chains
Disulphide bond linked
Tyrosine kinase domain on beta chains intracellularly
What are the target tissues of insulin?
Muscle
Adipose tissue
Liver
What is the role of the cytosolic domain of the insulin receptor?
Signalling
What is the affinity and specificity of the insulin receptor for binding insulin?
High affinity and specificity
What are the two models of how insulin activates its receptor?
Model 1: insulin induces change in orientation of receptor transmembrane domain
Model 2: yo-yo model = insulin induces changes in positioning of kinase domains by changing conformation of juxtamembrane segments of beta chain
What is the first step after insulin binds to its receptor?
Trans-autophosphorylation
- Multiple tyrosine residues phosphorylated in intracellular domains
Which domains in proteins recognise phosphorylated tyrosines?
SH2
PTB
What does the tyrosine phosphorylated insulin receptor bind?
Scaffold protein = insulin receptor substrate (IRS)1 via PTB domain
What happens when IRS1 binds the tyrosine phosphorylated insulin receptor?
Insulin receptor phosphorylates tyrosine residues in IRS1
What does tyrosine phosphorylation of IRS1 lead to?
Signal diversification - multiple signalling cascades activated
What is the impact of insulin on gene expression?
Both up- and down-regulates genes
Gives slow but relatively sustained impact
What is GSK3?
Protein that when active, inactivates glycogen synthase
When inactive, glycogen synthase can be active
What is the effect of insulin receptor signalling on GSK3?
Inactivates it > activated glycogen synthase
What is the impact of non-nuclear changes mediated by insulin receptor signalling?
Alters existing proteins > relatively rapid impact
How does insulin enhance glucose uptake in muscle and adipose tissue?
Changes trafficking of GLUT4 to cell surface > more GLUT4 on surface > more glucose enters cell
How can a protein without enzymatic activity; eg: IRS1, contribute to insulin signalling?
Acts as signalling scaffold/adaptor protein > diversification of signalling events
