Diabetic Adaptation 2 Flashcards
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).
Where do SLGT-2 inhibitors work
Kidney - excretes more urine
What happens to fat with insulin resistance
Decrease in GLUT4 which this decrease in glucose causes lipolysis which can damage hepatocytes and cause insulin resistance.
What role does PTP1B have in lipids
Stimulates leptin (fat hormone) signalling in the brain to regulate food intake
What happens if PTP1B KO occurs in peripheral tissue
Increased insulin sensitivity
What happens if PTP1B KO occurs in central tissues
Insulin sensitivity increase
Decreased body fat
Increased energy expenditure
Can PTP1B inhibit with drugs
MSI-1346 tried on ob/ob mice (model for obesity)
Fatty liver phenotype is improved
Glucose homeostasis is improved
Insulin signalling is improved
MSI-1436 effect in humans
Delconte
Glucose - decreases levels
Insulin - decreases levels
Shows it only works with chronic treatment
How does fenretinide work
Can decrease levels of serum retinol binding protein and therefore inhibit ceramide levels (ceramide is known to inhibit Akt)
What did PTP1IB knockout show
WIDER READING – Elchebly et al 1999
Increased tyrosine kinase phosphorylation of the insulin receptor and IRS proteins in muscle as PTP1B originally acts as a catalyst for dephosphorylation of the insulin receptor.
What affect do sulfolyureas and metformin have on the beta cells present in type 2 diabetics
WIDER READING – DeFronzo 2009
No significant protective effect on the functioning beta cells they have left due to rise in A1C
What is one disadvantage of sulfonlyureas and CVD
WIDER READING – Johnson 2002
Showing to have no effect on limiting and may even accelerate atherosclerotic formations
Give two benefits of exenatide
WIDER READING – defronzo 2009
Preserves B cell function and promotes weight loss through suppression on HGP
Give some benefits and risks of thiazolidones (pioglitazone)
WIDER READING – DeFronzo 2013
Benefits – reduce atherosclerotic plaque volume and slows progression of carotid intimal thickness
Risks – weight gain, fluid retention, bone fractures and bladder cancer
What activates Akt
WIDER READING – Boucher
PDK-1 and MTORC2 this phosphorylation of Akt allows the activation of man downstreat targets.
What does Akt do to FOXO
WIDER READING – Tzivion et al 2011
Phosphorylates it to take foxo out the nucleus and prevent it from expressing lipogenic and gluconeogenic genes.
What happened when akt was knocked out in mice and what does this show
WIDER READING - Lu et al 2012
Interestingly, although mice lacking Akt1 and Akt2 show severe hepatic insulin resistance and high levels of hepatic glucose production, these defects are normalized when Foxo1 is concomitantly ablated in the liver. This indicates that an additional pathway exists in the control of hepatic glucose metabolism beyond the Akt/Foxo1 axis, which allows for insulin mediated regulation of hepatic glucose production
How do DPP-4 inhibitors work
Wider reading – Nauck 2016
Preserve GLP-1 in active form for longer as normal physiological half-life is only 1-2 minutes.
How is metformin believed to work in the treatment for diabetes
WIDER READING – Hunter 2018
Lowering hepatic glucose production – inhibits mitochondrial respiratory complex I and thus elevate adenosine monophosphate levels (AMP) and activate AMP-activated protein kinase
This study also shows that AMP-inhibited enzyme FBP1 plays a major role in the actions of gluconeogenesis and metformin as metformin inhibits it – shown with a FBP1 AMP point mutation Knock in in mice.
What was subcutaneous exenatide (GLP-1-agonist) benefits post MI
WIDER READING – Woo 2013
Decreased infarct size
What was liraglutide (GLP-1 agonist) seen to do post-MI
WIDER READING – Chen 2015
Preserve LVEF after PCI
What was sitagliptin (DPP-4 inhibitor) seen to do in those with congestive HF
WIDER READING – Nogueira 2014
Improve left ventricular diastolic function
What does FOXO1 do to beta cells
WIDER READING – Kitamura - 2013
Inhibits beta cell replication but is needed to maintain its function and identity during high metabolic stress.
What does PTP1B deletion do to endothelial function
WIDER READING – Herre 2015
Protects it by compensating the reduction of nitric oxide bioavailabilty by increasing COX-2 mediated release of the vasodilator prostanoid PGI2 in PTP1B conditional knockout mice.
What does metformin do to GLP-1
WIDER READING – Rena 2017
Increase it
What role does TNF-alpha play in obesity-related diabetes and how was this shown.
Wider reading – Gokhan 1994
TNF-alpha is a key mediator in insulin resistance – used a rat model for obesity and insulin resistance after neutralzing TNF-alpha and this resulted in a marked increase in insuline stimulated autophosphorylation of the insulin receptor as well as IRS-1 phosphorylation in muscle and fat of these rats restoring them to near lean levels. Also lowered plasma glucose and FFAs.
No effects seen on IRS-1 or IR in the liver.
Shows that – TNF-alph
