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Metabolism 2 > Overnutrition > Flashcards

Overnutrition Flashcards

1
Q

What is the cause of overnutrition?

A

Overconsumption of calorie dense, highly palatable foods

Also
- Alternative external causes of metabolic defects

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2
Q

What are the major risk factors of overnutrition?

A
  • CVD
  • T2D
  • Metabolic syndrome
  • Cancer
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3
Q

What is metabolic syndrome?

A

A cluster of factors that result in an increased cardiovascular risk
- doubles risk of CVD
- increases risk of type 2 diabetes

Occurs in populations characterised by excessive nutrient intake and physical inactivity

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4
Q

What factors contribute to metabolic syndrome?

A
  • Atherogenic dyslipidemia –> hypercholesterolaemia
  • Hypertension
  • Pro-thrombotic state –> more likely to form blood clots
  • Pro-inflammatory state –> chronic inflammation
  • Insulin resistance and hyperglycaemia
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5
Q

Discuss type 2 diabetes

A

Component of metabolic syndrome
Defined by fasting glucose

  • Insufficient response (resistance) of tissues to glucose-lowering insulin
  • Over-production of insulin from pancreatic B-cells –> hyperinsulinaemia
  • F
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6
Q

Discuss type 2 diabetes

A

Component of metabolic syndrome
Defined by fasting glucose

  • Insufficient response (resistance) of tissues to glucose-lowering insulin
  • Over-production of insulin from pancreatic B-cells –> hyperinsulinaemia
  • Failure of pancreatic B-cells to produce insulin –> insulin dependent state
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7
Q

What is hyperglycaemia?
Link to type 2 diabetes

A

High levels of glucose in blood

In T2D with insulin resistance plasma glucose does not come back down to baseline after meals and when fasting
Has a significantly higher baseline

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8
Q

What is hyperinsulinaemia?
Link to T2D

A

High insulin levels

Mild insulin resistance –> higher spikes to insulin, to attempt to get blood glucose down to a reasonable level

Severe insulin resistance –> low insulin spike which cannot cope with the amount required for the level of blood glucose there is

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9
Q

What are the different nutrient states?

A

Fed –> post prandial (6-12 hours)
- digestion
- absorption

Fasted –> post-absorptive (overnight)
- digestion
- absorption
- storage
- use

Starved
- mobilised

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10
Q

What is the physiology of insulin action?

A

A peptide hormone secreted by pancreatic B-cells in fed state

Acts on multiple tissues, especially
- muscle
- liver
- white adipose tissue
- brain
Tissues communicate through the metabolites in between, the communication is what insulin is helping to signal

Orchestrates anabolic response –> nutrient storage

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11
Q

What metabolic processes does insulin action promote and suppress?

A

Promote
- Glycogenesis –> making glycogen
- Lipogenesis –> making lipid stores
- Glycolysis –> catabolism of glucose to promote other anabolic processes
- Protein synthesis

Suppresses
- Gluconeogenesis
- Glycogenolysis –> breaking down glycogen store
- Proteolysis –> protein breakdown
- Lipolysis –> breakdown of lipid stores

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12
Q

What is the direct insulin signalling pathway in muscle?

A
  1. Insulin activates insulin receptor tyrosine kinase –> phosphorylate IRS1
  2. Activation of Akt2
  3. Akt2 activates AS160 promotes translocation of GLUT4 containing storage vesicles (GSVs) to plasma membrane
  4. Entry of glucose into the cell
  5. Promotes glycogen synthesis and use of glucose –> ATP for other anabolic processes

Mobilisation of transporter proteins for glucose uptake from circulation

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13
Q

What is AKT2?

A

When activate by PI3K (which is phosphorylated IRS1 –> insulin binding to cell receptors), its then can target other intermediates to activate different pathways.
Metabolic pathway

GLUT4 –> Glucose uptake into cell
GSK3 –> Glycogen synthesis
FOXO –> Protein breakdown (transcriptional response)
mTOR –> Mitochondrial biogenesis and protein synthesis

These processes are affected by insulin synthesis

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14
Q

What is the direct action of insulin on the liver?

A

Glucose uptake into the liver is not insulin dependent

  1. Insulin activate insulin receptor - phosphorylates IRS1 and 2
  2. Activation of AKT2
  3. AKT2 in liver can
    - Promote glycogen synthesis
    - Suppress gluconeogenesis
    - Activate de novo lipogenesis (DNL)
    - Activate protein anabolism –> protein synthesis increased
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15
Q

What is the direct insulin action on white adipose tissue?

A
  1. Insulin activate insulin receptor –> phosphorylates IRS1 and 2
  2. Acetyl CoA –> Fatty acyl CoA
    - Stimulates glucose uptake by translocation of GLUT4
    - Suppresses lipolysis –> inhibits hormone-sensitive lipase –> key steps in breaking down triglycerides to form fatty acids and glycerol
    - Activates lipogenesis –> mobilises lipoprotein lipase –> delivering triglycerides to the cell to be converted into fatty acids
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16
Q

What is the indirect insulin action?
Fasting state
In healthy individuals

A

Interaction of lipolysis and gluconeogenesis

Under fasting conditions, the increase in adipose lipolysis causes an increase in hepatic gluconeogenesis.
- low levels of glucose
- lipid mobilisation –> stored triglycerides into glycerol and free fatty acids –> releasing nutrient store
- free fatty acids get taken up into the liver where its is oxidised and stimulates gluconeogenesis –> oxidisation creates acetyl CoA which stimulates pyruvate carboxylase which drives gluconeogenesis
- Glycerol also being used
- In absence of insulin, glycogen is broken down into glucose-6-phosphate which can then enter glycolysis

17
Q

What is the indirect action of insulin in the fed state? In healthy individuals
Interaction of lipolysis and gluconeogenesis

A

In fed conditions, the decrease in adipose lipolysis causes a decrease in hepatic gluconeogenesis
- Insulin released from pancreas and bind to white adipose tissue receptor
- Signals to store and stop fat breakdown (lipolysis)
- No longer increasing levels of free fatty acids and glycerol, causing a drop in Acetyl CoA
- Blocks pyruvate carboxylate –> preventing gluconeogenesis
- Increase in glycogen synthesis in the liver
- Decreasing glycogenlysis

What is happening with fat metabolism determines the whole body nutrient status

18
Q

What is insulin resistance?

A

When normal plasma insulin concentration fails to result in co-ordinated glucose lowering response of tissues
- More insulin required to achieve the same outcome, ability to produce not affected
- Can be a component of chronic disease e.g. cancer
- Not that the cells are no longer sensitive to insulin, they just require more to achieve the same job –> response blunted

Affects multiple organs
- liver
- muscle
- adipose
- brain
- pancreas

19
Q

What occurs in muscle insulin resistance?

A

One of the earliest events in the development of insulin resistance
Major driver of hyperglycaemia in obesity
Common feature of many chronic diseases such as CKD, chronic heart failure, acute critical illness, cancer
As muscle is so large, despite not producing that much glucose, in the development of T2D, it has a significant driving force of around 60% of IR.
20-30% of whole body glucose turnover in fed state is handled by muscle

Obesity/ T2D resistance of glycogen synthesis and glycolysis to insulin stimulation –> muscle doesn’t store glycogen as well and glycolysis becomes less sensitive to the affects of insulin

Proximal (close to receptor) insulin signalling defects impair glucose uptake
- blocks AKT2 response

20
Q

How does a insulin-sensitive muscle cell compare to insulin resistant muscle cell?

A

Insulin resistant muscle cell
- less receptors present
- insulin can bind to receptor however it cannot transmit signal leading to no activation pathway of transporter proteins –> less tyrosine phosphorylation, lower receptor substrate associated PI3 kinase activity and low phosphorylation of AKT2 –> signals cannot pass on as well
- failure to translocate transporters and uptake glucose

21
Q

What happens in the liver during insulin resistance? Compared to insulin-sensitivity
In fed state

A

Insulin-sensitive liver
- Promotes glucose storage –> increased glycogenesis
- Suppresses glucose production –> decreased glycogenolysis, decreased gluconeogenesis

Insulin resistant liver
- Smaller glycogen fluctuations
- Glucose production promoted (direct and indirect)
- If adipose tissue now IR, then the signal cannot transduce to block lipolysis, so free fatty acids and glycerol still being made
- No signal to decrease glyconeogenesis –> still high levels of Acetyl CoA which is stimulating Pyruvate carboxylate
- Increased glyconeogenesis

22
Q

How does lipid accumulation link with insulin resistance?

A

Elevated circulating free fatty acids –> liver can create its own fat
Accumulation of lipid (triglycerides) in liver (and muscle)
In an insulin resistance state, high circulating FFA drive the liver to accumulate triglycerides, and muscle. Lipid droplets in liver and muscle.
Can develop into Non-alcoholic fatty liver disease present 2/3 obese individuals and almost all obese individuals with T2D

Plasma FFA do not drop to normal baseline after a meal.
- Adipose tissue increases in number and size –> where fat comes from

23
Q

How is lipid accumulation a driving force for insulin resistance?

A

Lipotoxicity –> toxic amount of triglycerides

Healthy fed
- Dietary fat from triglycerides, enter circulation bound to chylomicrons
- Taken up by adipose tissue and muscle
- Some taken up by liver where they are converted into fatty acids
- Lipogenesis occurring –> oxidised in liver, or being synthesis triglycerides

Healthy fasted
- Less entry of TG from intestine
- Adipose tissue store TG
- Mobilised into FA
- Use by the liver

Overnutrition and IR
- Larger adipose tissue mass (IR of AT - no break on lipolysis)
- Significant amount of FA in liver forming large amount of TG in liver and accumulates
- Decrease in FA oxidation due to blockades either with mitochondrial dysfunction or with some allosteric blockade at Acetyl CoA

  • Increase uptake of FFA from lipolysis (adipocytes)
  • De novo lipogenesis
  • Low mitochondrial B FA oxidation
  • Redirection of fa to TG synthesis
24
Q

What is the ectopic lipid hypothesis?

A

Fat stores outside white adipose tissue/ subcutaneous adipose tissue are known as ectopic sites.
Association between individuals who are lean and insulin sensitive as they are not storing fat in liver or muscle but they can be insulin resistance as well as they have low levels of adipose in subcutaneous area but lipid or fat in the muscle.

Toxicity of fat depends on its location
- abdominal adipocity % –> links to IR
- due to abdominal fat having a faster access to the liver and fat drains into the hepatic portal vein –> more cytokine leakage –> inflammation

25
Q

What molecular mechanism are involved in lipid-induced IR?

A

TG and diacylglycerol synthesis –> DAG/ PK6
High levels of SFA e.g. Palmitate has interactions with Ceramide (AKT signalling pathway)
Fatty acid flux –> incomplete FA oxidation –> Aceylcarnitine formation –> Reactive oxygen species from mitochondrial over load
Inflammation

26
Q

What is the role of inflammation in lipotoxicity?

A

White adipose tissue is the site of low grade chronic inflammation result of cell death from expanding adipocytes mass. Core of adipose tissue becomes hypoxic
Adipocyte death chemo-attract adipose tissue macrophages for phagocytosis
Adipocyte death also releases fat into the circulation
40% of all cells in obese adipose tissue are ATM
Visceral adipose tissue more pro-inflammatory that white adipose tissue
Adipose tissue macrophages secrete pro-inflammatory cytokines
- TNF-a, IL-1B, IL-6 likely main mediators produced by ATMs
- TNF-a signalling activates c-Jun N-terminal kinase and IkB kinase
Inhibit white adipose tissue receptor signalling by serine phosphorylation of insulin receptor substrate IRS1
Thus cytokine-mediated adipose lipolysis exacerbates IR.

27
Q

How does insulin resistance become T2D?

A

Fasting hyperglycaemia due to insufficient response of tissues to glucose-lowering insulin

Postprandial insulin response
- secreted from pancreatic B cells in response to elevated glucose and amino acids
- acts on tissue
- cleared out by liver and kidneys

Insulin resistant individuals
- elevated insulin response
- impaired insulin clearance
- hyperinsulinaemia –> mimics insulin growth factor 1

28
Q

What are the models of hyperinsulinaemia?

A

Early beta cell defects

Insulin release depends on the insulin sensitivity of tissues
Highly sensitive tissues don’t need to secrete that much insulin
As beta failure occurs, tissues are becoming more insulin resistant and gradually as IR progresses into T2D, there is poor insulin sensitivity and secretion.

29
Q

What is B-cell failure?

A

As beta failure occurs, tissues are becoming more insulin resistant and gradually as IR progresses into T2D, there is poor insulin sensitivity and secretion.

Causes:
- Glucolipotoxicity
- Inflammation
- Genetic susceptibility
Combined with
- Increased secretory demand
Lead to
- Bioenergetic failure?
- Oxidative stress? –> Mitochondrial dysfunction
- Signalling dysfunction?

Bioenergetic failure drive B cells because, energy metabolism in B cells is driven by ATP supply, so the presence of glucose is used to stimulate production. Glucose taken up into the cell, metabolised by mitochondria that increases the ATP ratio and blocking the ATP sensitive potassium channel causing depolarisation which increasing the calcium influx which exports insulin from the cell.
Susceptible to mitochondrial dysfunction.

Metabolism 2 (6 decks)

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