8 - Insulin Flashcards
Fasting glucose level
3.5-5 mmol/L
Glucose level after meals
<8mmol/L
What can the brain not do
Synthesise or store glucose
Extract glucose at low concentrations
What percent of pancreas cells are endocrine and exocrine
Endocrine - 2%
Exocrine - 98%
What do alpha cells produce
Glucagon
What do beta cells produce
Insulin
in islets of langerhans
Delta cells
Somatostatin
PP cells
Pancreatic polypeptide
Epsilon cells
Ghrelin
Structure of insulin
2 chains linked by 3 disulphide bonds
Which form of insulin is active
Monomer
Dimers when insulin increases
What is the stored form of insulin
Hexamer
What causes a dimer to hexamer
Zinc and pH
How is insulin synthesised
Pancreatic B cells –> preproinsulin in ER (110) –> proinsulin (86) –> indergoes maturation into active insulin via cellular endopeptidases in golgi A
o Endopeptidases cleave off C peptide from insulin by breaking the bonds between lysine 64 and arginine 55 + arginine 31 and 32 (21+30).
How long is preproinsulin
110
How long is proinsulin
86
What controls production of insulin
Transcription from insulin gene
mRNA stability
mRNA translation
post-translational modifications
How does glucose enter B cells
via GLUT 1 (humans) GLUT 2 (rats)
What is the function of glucokinase
Acts as the glucose sensor for insulin secretion
When is insulin secreted
When the levels exceed 5mm
What is the process of insulin being secreted
Glucose –> G6P –> Pyruvate (glycolysis) –> Krebs cycle –> generates ATP –> increases ATP:ADP ration in the cell –> at sub-stimulatory glucose concentrations, Katp channels open –> resting potential is maintained at hyperpolarised level –> increase in Katp closing and membrane depolarisation –> voltage gated calcium channels open –> insulin secretion
What are the 2 phases of insulin secretion
1) Rapid release in response to raised BG
2) Sustained, slow release of newly formed vesicles
What other signals can potentiate insulin release
Arginine Leucine GLP-1 Fatty Acids Ach release via phospholipase C CCK
How does arginine potentiate insulin release
Directly depolarises the membrane
How does leucine potentiate insulin release
Act through allosteric activation of glutamate dehydrogenase
can be transaminated –> KIC –> Acetyl CoA
How does GLP-1 enhance insulin secretion
Inhibits glucagon
Promotes satiety
promotes B cell differentiation and can restore their function
How can you amplify insulin secretion with amino acids
Intracellular catabolism of amino acids increase ATP/ADP ratio
Incretins
GLP-1 secretion
GLP-1 (7-36)/exendin-4 administration stimulates insulin secretion through GPCR-1 using glucose.
Role of phosphorylated inositol
Phospholipase C cleaves PIP2 to IP3 + diacylglycerol
IP3 binds to receptor protein in ER allowing for the release of calcium from ER (increases Ca –> increase insulin release)
What activates the insulin receptor
Insulin
IGF-1
IGF-II
What type of receptor is insulin receptor
transmembrane tyrosine kinase receptor
Activation of insulin receptor
Insulin binds to extracellular alpha subunit on IR
Conformational change
Activates tyrosine kinase within the cell
Activated kinase domain autophosphorylates tyrosine residues on C-terminus of the receptor + tyrosine residues in the adaptor protein (IRS)
Relocation of IRS then phosphorylation of P13K
P13K activates and reloactes PIP2 to PIP3
causes change in Akt
phosphorylation of downstream effectors
What does insulin do in muscles
Stimulate glycogen synthesis via glycogenesis
Stimulates translocation of GLUT4 to muscles
Function of Akt
increases glucose transport and glycogen synthesis
- induces translocation of GLUT4 to plasma membranes
- phosphorylates and inactivates glycogen synthase kinase (GSK)
How does insulin stimulate glucose uptake into adipocytes and lipogenesis
Glucose used for alpha glycerol phosphate that supplies glycerol to triglycerides
Insulin inhibits lipolysis
- Inhibits HSL
- Inhibits hydrolysis of triglycerides and FA release into blood
Insulin function in the liver
Enhances glucose uptake increases glucokinase activity Increases glycogen synthesis (100g stored glycogen) Lipids exported as lipoproteins Insulin inhibits gluconeogenesis
Other insulin function
Protein synthesis Transports AA into cells Increases translation of mRNA to new proteins Inhibits catabolism of proteins Promotes K+ uptake
What occurs during a fast
Glycogen is broken down via glycogen phosphorylase
Increase in gluconeogenesis and glycogenolysis (AA and glycerol used)
Fatty acids go through B-oxidation to produce acetyl coA from acyl CoA
acetyl CoA converted into ketone bodies
Lactate to pyruvate via cori cycle
what converts acetyl coa to ketone bodies
Thiolase
HMG CoA synthase
How to turn off insulin
- Endocytosis and degradation of the receptor bound to insulin
- Dephosphorylation of the tyrosine residues by tyrosine phosphatases
- Decrease in the number of receptors also leads to reduced insulin signalling
- Serine/Threonine kinases reduce the activity of insulin (acts on IRS)
Insulin resistance
- Reduced response in target tissue due to the IRS phosphorylating the threonine/serine instead of the tyrosine.
o Downstream activation of PI3K does not occur
