Diabetic Adaptation 2 Flashcards
(49 cards)
What receptor type is required for insulin
A transmembrane receptor called tyrosine kinase - its ligand is insulin (peptide hormone) which binds extracellularly as it is hydrophilic and cant enter cell membrane.
What happens when insulin binds to tyrosine kinase
Causes phosphorylation and IRS binds and is then phsophorylated causing further complex signalling events, the most important is Akt.
This process can be inhibitory too.
How does insulin stimulate glucose uptake
The phosphorylated IRS causes Akt transcription to inactivate AS160 (G protein inhibitors)
These Rab GTP proteins activate GLUT4 recruitment to take in glucose to cells.
What happens to the glucose once it enters cells
Glycogen synthase is the enzyme that catalyses the last step in the synthesis of glycogen.
What inhibits glycogen synthase
GSK3 phosphorylates it and inhibits it.
What inhibits GSK3
GSK3 is inhibited by Akt which in turn dephosphorylates glycogen synthase and promotes glycogen formation.
What is the role of FOXO1
Normally unphosphorylated in nucleus and bigns to G6Pase promoter to increase transcription rate.
This promotes hepatic gluconeogenesis- ( (increases the rate of hepatic glucose production)
What does insulin (via Akt) do to FOXO1
Phosphorylates FOXO1 which takes it out of the nucleus and it is degraded.
This therefore decreases hepatic glucose production as decreases hepatic gluconeogeneisis by inhibiting G6Pase.
How does insulin cause storage processes of nutrients (lipids, DNA proteins etc) through Akt
Akt phosphorylates TSC1 and 2 which inactivates them leading to mTORC1 activation.
mTORC1 activation promotes synthesis of protien, lipids and DNA.
How does insulin resistance occur
Raise in serum insulin
Negative feedback causes insulin receptor decrease via inhibition of gene expression and removal from cell surface
Post receptor defect causing negative feedback downstream of insulin receptor
What is the role of S6 kinase 1
Inhibit Act by phosphorylation of IRS1 by Ser/Thr on tyrosine kinase receptor
IRS1 now inhibits binding of PI3K which promotes protein degradation and insulin resistance
How is IRS phosphorylation by Ser/Thr activated
Free fatty acids, TNF alpha and Il6 all phosphorylate more kinases and phosphorylate IRS 1
What is PTP1B
A negative regulator of the insulin receptor, so does the opposite of a kinase (dephosphorylates). This dampens insulin signalling.
It is widely expressed.
When is PTP1B increased
Obesity
Inflammation
What happened when PTP1B KO occured in mice
Insulin sensitive and have enhanced and prolonged insulin receptor phosphorylation
No affect on adipose tissue
Increased glucose uptake in skeletal muscle and the liver
What was the phenotype of PTP1B KO mice
Lean with increased metabolic rate, reduced adipose tissue mass and are resistant to diet induced obesity.
What is metabolic syndrome
Hypertension
CVD
Diabetic nephropathy
Cancer
NAFLD
What ways are used to look at body fat specifically
BMI not specific enough so use -
Skinfold calipers
DXA
hydrostatic weighing
Waist circumference
Waist/hip ratio
What is the worst type of fat
Increased visceral fat (fat covering organs) - higher risk of diabetes and metabolic syndrome
Subcutaneous fat not so much.
What factors influence where fat sits in the body
Gender/sex hormones - changes with menopause
Medication - thiazolidinediones decrease visceral fat
What does insulin do to fat
Inhibits lipolysis therefore promoting fat storage.
Storage form - Triglycerides (glycerol and fatty acids)
How does visceral fat increase insulin resistance
Lipolysis results in increase FFA which goes from the visceral fat into the portal vein and into the liver. When it is in the liver it causes insulin resistance as described previously with PTP1B
What is the lipid overflow-ectopic fat model
Fatty liver causing increased lipoprotein release into circulation which –>
Increases hepatic insulin resistance through increased hepatic gluconeogenesis and fasting hyperglycaemia which –>
Causes B-cell expansion which causes hyperinsulinaemia which is linked to hypertension
Flawed though as only 20% liver fat is from systemic fat and not visceral fat so unsure.
How does metformin work
Improves glucose uptake in muscles - causing mild metabolic stress in muscles which results in increases the ATP/ADP ratio which promotes K ATP channels closing –> depolarisation with Ca influx and insulin release
Still not fully understood.
Also believed to inhibit FBP1 (activator of gluconeogenesis).
