Insulin Flashcards
What is the overall function of insulin?
Main hormone controlling intermediate metabolism having actions of liver, muscle and fat
Conserves fuel by enhancing uptake, utilisation and storage of glucose
Describe the insulin receptor
Receptor is a large transmembrane glycoprotein complex
Consists of 2 alpha and 2 beta subunits linked by disulphide bridges
Describe alpha and beta subunits of the insulin receptor
Alpha subunits - extracellular and have an insulin binding domain
Beta subunits - transmembrane proteins with intrinsic tyrosine kinase activity
What technique is used to determine cellular localisation of the insulin receptor?
Immunocytochemistry
What technique is used to detect insulin receptor mRNA in specific brain regions?
In situ hybridisation
What technique is used to determine specific localisation of insulin receptor mRNA and protein in different brain regions?
Western blots and RT-PCR
How does peripherally derived insulin get into the brain?
Active transport across the BBB
- saturable insulin transporter exists
- insulin transporter is a regulated system
Insulin may also be released locally in the CNS - insulin mRNA is expressed in neurons and released from neurons by depolarisation
What does insulin do in the periphery?
Regulates glucose metabolism
What does insulin do in the CNS?
Some studies suggest insulin mediates cerebral glucose uptake but only in glial cells, not in neurons
Describe the hypothesised role of insulin in learning and memory
Long term hyper-insulinemia is a risk factor for dementia
High insulin levels result in resistance to insulin - leading to reduced levels of insulin reaching the brain
Insulin administration to healthy patients improves memory
What learning and memory processes has insulin been shown to influence?
IRs are concentrated in brain regions invovled in memory (hippocampus and amygdala)
Insulin induces changes in excitatory synaptic strength
Injection of streptozotocin (a diabetic inducing agent) into brain induces significant memory impairment
Defective insulin action reported in AD
In T2DM impairment of cognitive function is marked
What effect does insulin have on NMDA receptor function?
Insulin facilitates native NMDAR mediated responses (hippocampal) and recombinant NMDAR mediated currents
Insulin selectively enhances NR1/NR2A and NR1/NR2B recombinant NMDAR isoforms
What does binding of insulin to the alpha subunit of the IR cause?
Autophosphorylation of tyrosine residues on beta subunits which stimulates intrinsic tyrosine kinase activity of the insulin receptor
The phosphorylated IR triggers activation of different signalling cascades
What do insulin receptor tyrosine kinase inhibitors do to signalling pathways mediating insulin facilitation of NMDA receptors?
Insulin receptor tyrosine kinase inhibitors block signalling pathways mediating insulin facilitation of NMDA receptors
What do PKC inhibitors and Src TK inhibitors do to insulin action?
They block insulin action
What does insulin do to surface expression of NMDA receptors?
Enhances surface expression of NMDARs
How does insulin affect NMDAR induced calcium influx?
Insulin does not affect basal calcium levels
Insulin potentiates NMDA induced calcium influx in a reproducible and reversible manner
What do PI3 kinase and MAPK inhibitors do to insulin action?
They attenuate the actions of insulin
What effect does insulin have on excitatory synaptic transmission?
Insulin facilitates NMDAR mediated synaptic transmission in hippocampus
This is likely to promote induction of LTP
Insulin depresses AMPAR mediated EPSCs in hippocampal neurons (by reducing surface AMPAR expression). This may contribute to LTD
What effect does insulin have on GluA1 and GluA2 surface expression?
Insulin reduces GluA2 but not GluA1 surface expression
What effect does insulin have on endocytosis of GluA2 subunits and what effect does this endocytosis have on excitatory synaptic transmission?
Insulin accelerates endocytosis of GluA2 subunits
Increased endocytosis results in LTD of excitatory synaptic transmission
