When is diabetes diagnosed?
When blood glucose levels are not controlled properly
Prevents hyperglycemia and therefore diabetes
High blood glucose levels in the body
Major function of insulin?
To prepare the body for incoming nutrients
Promoting storage, thereby preventing nutrient toxicity
What 3 processes does insulin do within the cell?
Insulin stimulates glucose uptake into the cell.
Turns off glucose production after a meal.
Stimualtes glucose storage as glycogen
7 Major diseases caused by insulin signalling?
Type 2 diabetes: defective insulin signalling.
Heart disease: abnormal vascular signalling
Obesity: abnormal appetitie and thermogenesis
Immune disease: defective immunoreactivity.
Neurodegeneration: abnormal apoptosis
Cancer: abnormal growth signal
Epilepsy: abnormal neuronal signalling
The process of signalling?
External signal: such as hormone or neurotransmitter- transfers info between cells.
Receptor: functions to detect the external signals.
Transducer: Receives info from receptors and transform it into different types of info.
Effectors: Specific cellular process.
Why is intracellular communication needed?
Respond to environemnt
Adjust to state of cell/tissue (DNA damage, cell cycle etc)
What is an insulin receptor?
Tyrosine kinase associated receptor
alpha and beta domains.
Receptor tyrosine kinase classes are defined by?
How many classes are there?
Defined by their ligands
Lots and lots of classes
eg. EGF, FGF, Insulin
Reaction to get from ionositol into phosphoinositide and then into PI kinase?
Inositol -----(ATP->ADP)---> Phosphoinositols
Specifically phosphorylates 3-position of ring.
PI3-kinase used as?
Used to phosphorylate different phosphatidyl inositols.
This is the major reaction involved in insulin and GF signalling
What two enzymes are in balance for the ratio PIP2:PIP3?
PTEN (lipid phosphatase)
Additionally SHIP (5-Ppase)
Name some of the physiological agents that induce PIP3 levels?
What does PIP3 bind to?
Binds to the PH domain
Alters their function
Key to transucing insulin action.
What group can proteins get phosphorylated on?
Any hydroxyl group
Introduces a large negative charge into the protein structure
Serine/Threonine Protein Kinases?
Primarily cytosolic and nuclear.
Tyrosine Protein Kinases?
Primarily receptor linked
Dual specifcity protein kinases?
Small number of protein kinases
Can phosphorylate Ser/Thr or tyrosine.
Effects of protein phosphorylation?
Interaction with other proteins.
What other conditions do specific protein kinase inhibitors treat?
Early trials: immunological, metabolic and neurological diseases.
For the treatment for insulin resistance
the two specific pathways involved in insulin action?
1) PI3- kinase pathway
2) MAP kinase pathway
What is the P13-kinase pathway?
Insulin binds to receptor
Causing a phosphorylation effect on the receptor.
This allows IRS to bind and become activated (by phosphorylation)
This binds to PI3-K which activates it.
Stimualtes the PIP2 to PIP3 reaction
What is the outcome of producing PIP3
Produces downstream effects
Such as PDK1
Insulin activation of protein kinase B (AKT)
Protein Kinase B (AKT)
Major enzyme in PIP3 signalling.
Key component of insulin and GF.
MAP kinase Signalling?
Insulin binds to receptor.
Phosphorylation of the receptor.
Causes the IRS to bind.
This stimulates the activation of Ras (using ATP)
Activation of Raf
Activation of MAPKK (by phosphorylation)
Stimulates the activation of p44MAP kinase
MAP kinase does?
Stimulation of downstream affectors.
Gene transcription growth (including CREB, MSK)
Neuronal strcuture: MAP2
GSK3 (an inhibitor of the glycogen synthesis)
Glyconeogenic gene expression
Protein tyrosine phosphatase 1B?
Turns off the insulin signalling
By interferring with the MAP kinase and PI3 kinase pathway
Negative feedback within MAP kinase pathway?
Downstream production of MAPK phosphatas
Inhibits the MAPK.
Type 2 diabetes are found to have what wrong with these pathways?
Defective insulin signalling.
Could be due to insulin antagonist (PTP1B, IRS1 kinase)
What causes PIP3 to break down to PIP2?
Reduced sensitivity to insulin
Molecular, cellular , tissue or whole organism
Therapy to fix and re-sensitive to insulin
Need a good diagnosis on what has went wrong as there is numerous reasons why someone has become insulin resistant.
Naem the 3 Regulators of insulin signalling ?
Why are they important?
- PTP1B inhibitors
- GSK-3 inhibitors
- AMPK activators
Important for current research to overcome insulin resistance
What does PTP1B do?
Turns off insulin signalling.
Therefore no longer MAP kinase or PI3 kinase pathway
Inhibitors of PTP1B activity?
Increase the insulin receptor activity.
Being developed for the treatment of diabetes.
Being developed for the treatment of diabetes.
Restore the effect of insulin on GSK3 activity.
Insulin and diabetes?
In diabetes there is a reduced insulin sensitivity
Leads to enhanced insulin production to compensate.
Asymptomatic: no symptoms.
When can type 2 diabetes be diagnosed?
When the pancreas can no longer make enough insulin to overcome the insulin resistance.
Difference between type 1 and type 2 diabetes?
The pre-diabetes stage.
T2 patients have relatively high levels of insulin but the cells are resistant to it while T1 patients make little insulin.
What are the risk factors for T2 diabetes?