Diabetic Adaptation 2 Flashcards

1
Q

What receptor type is required for insulin

A

A transmembrane receptor called tyrosine kinase - its ligand is insulin (peptide hormone) which binds extracellularly as it is hydrophilic and cant enter cell membrane.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What happens when insulin binds to tyrosine kinase

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How does insulin stimulate glucose uptake

A

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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What happens to the glucose once it enters cells

A

Glycogen synthase is the enzyme that catalyses the last step in the synthesis of glycogen.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What inhibits glycogen synthase

A

GSK3 phosphorylates it and inhibits it.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What inhibits GSK3

A

GSK3 is inhibited by Akt which in turn dephosphorylates glycogen synthase and promotes glycogen formation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the role of FOXO1

A

Normally unphosphorylated in nucleus and bigns to G6Pase promoter to increase transcription rate.

This promotes hepatic gluconeogenesis- ( (increases the rate of hepatic glucose production)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What does insulin (via Akt) do to FOXO1

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How does insulin cause storage processes of nutrients (lipids, DNA proteins etc) through Akt

A

Akt phosphorylates TSC1 and 2 which inactivates them leading to mTORC1 activation.

mTORC1 activation promotes synthesis of protien, lipids and DNA.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

How does insulin resistance occur

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the role of S6 kinase 1

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How is IRS phosphorylation by Ser/Thr activated

A

Free fatty acids, TNF alpha and Il6 all phosphorylate more kinases and phosphorylate IRS 1

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is PTP1B

A

A negative regulator of the insulin receptor, so does the opposite of a kinase (dephosphorylates). This dampens insulin signalling.

It is widely expressed.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

When is PTP1B increased

A

Obesity
Inflammation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What happened when PTP1B KO occured in mice

A

Insulin sensitive and have enhanced and prolonged insulin receptor phosphorylation

No affect on adipose tissue

Increased glucose uptake in skeletal muscle and the liver

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What was the phenotype of PTP1B KO mice

A

Lean with increased metabolic rate, reduced adipose tissue mass and are resistant to diet induced obesity.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is metabolic syndrome

A

Hypertension
CVD
Diabetic nephropathy
Cancer
NAFLD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What ways are used to look at body fat specifically

A

BMI not specific enough so use -

Skinfold calipers
DXA
hydrostatic weighing
Waist circumference
Waist/hip ratio

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is the worst type of fat

A

Increased visceral fat (fat covering organs) - higher risk of diabetes and metabolic syndrome

Subcutaneous fat not so much.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What factors influence where fat sits in the body

A

Gender/sex hormones - changes with menopause
Medication - thiazolidinediones decrease visceral fat

21
Q

What does insulin do to fat

A

Inhibits lipolysis therefore promoting fat storage.
Storage form - Triglycerides (glycerol and fatty acids)

22
Q

How does visceral fat increase insulin resistance

A

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

23
Q

What is the lipid overflow-ectopic fat model

A

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.

24
Q

How does metformin work

A

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).

25
Q

Where do SLGT-2 inhibitors work

A

Kidney - excretes more urine

26
Q

What happens to fat with insulin resistance

A

Decrease in GLUT4 which this decrease in glucose causes lipolysis which can damage hepatocytes and cause insulin resistance.

27
Q

What role does PTP1B have in lipids

A

Stimulates leptin (fat hormone) signalling in the brain to regulate food intake

28
Q

What happens if PTP1B KO occurs in peripheral tissue

A

Increased insulin sensitivity

29
Q

What happens if PTP1B KO occurs in central tissues

A

Insulin sensitivity increase
Decreased body fat
Increased energy expenditure

30
Q

Can PTP1B inhibit with drugs

A

MSI-1346 tried on ob/ob mice (model for obesity)

Fatty liver phenotype is improved
Glucose homeostasis is improved
Insulin signalling is improved

31
Q

MSI-1436 effect in humans

Delconte

A

Glucose - decreases levels
Insulin - decreases levels

Shows it only works with chronic treatment

32
Q

How does fenretinide work

A

Can decrease levels of serum retinol binding protein and therefore inhibit ceramide levels (ceramide is known to inhibit Akt)

33
Q

What did PTP1IB knockout show

WIDER READING – Elchebly et al 1999

A

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.

34
Q

What affect do sulfolyureas and metformin have on the beta cells present in type 2 diabetics

WIDER READING – DeFronzo 2009

A

No significant protective effect on the functioning beta cells they have left due to rise in A1C

35
Q

What is one disadvantage of sulfonlyureas and CVD
WIDER READING – Johnson 2002

A

Showing to have no effect on limiting and may even accelerate atherosclerotic formations

36
Q

Give two benefits of exenatide
WIDER READING – defronzo 2009

A

Preserves B cell function and promotes weight loss through suppression on HGP

37
Q

Give some benefits and risks of thiazolidones (pioglitazone)
WIDER READING – DeFronzo 2013

A

Benefits – reduce atherosclerotic plaque volume and slows progression of carotid intimal thickness
Risks – weight gain, fluid retention, bone fractures and bladder cancer

38
Q

What activates Akt
WIDER READING – Boucher

A

PDK-1 and MTORC2 this phosphorylation of Akt allows the activation of man downstreat targets.

39
Q

What does Akt do to FOXO
WIDER READING – Tzivion et al 2011

A

Phosphorylates it to take foxo out the nucleus and prevent it from expressing lipogenic and gluconeogenic genes.

40
Q

What happened when akt was knocked out in mice and what does this show
WIDER READING - Lu et al 2012

A

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

41
Q

How do DPP-4 inhibitors work
Wider reading – Nauck 2016

A

Preserve GLP-1 in active form for longer as normal physiological half-life is only 1-2 minutes.

42
Q

How is metformin believed to work in the treatment for diabetes
WIDER READING – Hunter 2018

A

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.

43
Q

What was subcutaneous exenatide (GLP-1-agonist) benefits post MI
WIDER READING – Woo 2013

A

Decreased infarct size

44
Q

What was liraglutide (GLP-1 agonist) seen to do post-MI
WIDER READING – Chen 2015

A

Preserve LVEF after PCI

45
Q

What was sitagliptin (DPP-4 inhibitor) seen to do in those with congestive HF
WIDER READING – Nogueira 2014

A

Improve left ventricular diastolic function

46
Q

What does FOXO1 do to beta cells
WIDER READING – Kitamura - 2013

A

Inhibits beta cell replication but is needed to maintain its function and identity during high metabolic stress.

47
Q

What does PTP1B deletion do to endothelial function
WIDER READING – Herre 2015

A

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.

48
Q

What does metformin do to GLP-1
WIDER READING – Rena 2017

A

Increase it

49
Q

What role does TNF-alpha play in obesity-related diabetes and how was this shown.

Wider reading – Gokhan 1994

A

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