Normal and deregulated metabolism Flashcards
Insulin promotes the intracellular uptake of which ion? [1]
K+
Which tissues use glucose as fuel?
Which organ is the exception and what does it use as a fuel source instead? [1]
Which tissues use glucose as fuel?
All tissues
Which organ is the exception and what does it use as a fuel source instead? [1]
Liver: fatty acid oxidation instead
How can triglycerides be used to produce ATP?
Triglycerides broken down by lipase in fatty acids and glycerol
Fatty acids can make acetyl coA via beta oxidation and therefore ATP
How much glucose does the brain cosume per day? [1]
Why is a steady glucose supply important for the brain? [1]
How much glucose does the brain cosume per day? [1]
120 g
Why is a steady glucose supply important for the brain? [1]
Brain has no store of glucose so must be supplied
How does body create fuel source at:
a) post absorb. state?
b) when glucose stores are used up?
c) continued fasting
d) further fasting
Post absorbative state:
- Muscle and adipose tissue reduce their glucose utilisation
If glucose stores are used up (24hr store) moves:
- triglyceride stores: fatty acids are used to make ATP via beta oxidation in cartinine shuffle.
- glucose made at the liver via gluconeogensis (using lactate, amino acids or glycerol) to continue a glucose supply
If continued fasting: ketogenesis occurs:
- Brain and RBC use glucose from hepatic and renal gluconeogenesis
- Other tissues use keto molecules as an additional fuel source
Prolonged fasting:
- Brain reduces glucose use; uses some ketone bodies (but glucose is still required)
- RBC use glucose from renal and hepatic GNG
How does body create fuel source at:
a) post absorb. state?
b) when glucose stores are used up?
c) continued fasting
d) further fasting
Post absorbative state:
- Muscle and adipose tissue reduce their glucose utilisation
If glucose stores are used up (24hr store) moves:
- triglyceride stores: fatty acids are used to make ATP via beta oxidation in cartinine shuffle.
- glucose made at the liver via gluconeogensis (using lactate, amino acids or glycerol) to continue a glucose supply
If continued fasting: ketogenesis occurs:
- Brain and RBC use glucose from hepatic and renal gluconeogenesis
- Other tissues use keto molecules as an additional fuel source
Prolonged fasting:
- Brain reduces glucose use; uses some ketone bodies (but glucose is still required)
- RBC use glucose from renal and hepatic GNG
What happens to electrolytes during starvation? [1]
Which electrolytes in particular? [2]
Loss of electrolytes: particularly phosphate and potassium
(insulin controls the uptake of K into the cell)
What is refeeding syndrome?
Which deficiences are like to get? [3]
What can it lead to? [2]
Upon refeeding, synthesis of glycogen, triglycerides, proteins
This requires intracellular ions, however these have been depleted throughout starvation. Get transport of ions (particularly K) intracellularly.
Causes a depletion of serum ion levels: can get Hypophosphataemia, hypokalamia, thiamine deficiencies
Leading to congestive heart failure and peripheral oedema
During the fasting state which processes are occurring in
a) muscle
b) liver
c) adipose
Muscle
* Glycogen is **broken down **(GLYCOGENOLYSIS) to provide ATP
Liver:
* GLYCOGENOLYSIS in liver releases glucose into bloodstream (reserve depleted in 24 h)
* GLYCOLYSIS is inhibited in the liver.
* Liver synthesises new glucose (GLUCONEOGENESIS) from amino acids, lactate, glycerol
Adipose tissue:
* Triglycerides are broken down in adipose tissues (LIPOLYSIS) – to provide glycerol (used in gluconeogenesis) and fatty acids
In post-absorb / fasting state which substance is used by the liver as a substrate for GNG? [1]
In post-absorb / fasting state which substance is converted to ketone bodies by the liver? [1]
Oxaloacetate is used by the liver as substrate for gluconeogenesis
Excess acetyl-CoA is converted into ketone bodies by the liver (KETOGENESIS), which then used to produce ATP
What type of receptor is insulin receptor? [1]
Tyrosine kinase receptor
Explain how insulin works to allow glucose into cell in healthy cells? [5]
- Insulin binds to insulin receptor
- Autophosphorylation of the receptor occurs
- IRS is phosphorylated by the receptor on Tyrosine residues
- Phosphorylated IRS can now bind to PI3K which moves from the cytoplasm
- Causes PIP2 to PIP3
- Causes activation of AKT pathwayand GLUT 4 to move to membrane
GLUT4 transporters are now inserted into the membrane
Glucose can cross the membrane & it can be stored
How can insulin resistance occur? [6]
Decrease in the number of insulin receptor
Decrease in the catalytic activity of the receptor
Increased activity of Tyrosine phosphatases
Decreased levels and function of GLUT4
Increased Ser/Thr phosphorylation of the receptor or of IRS
Decreased PI3K/Akt activity
Explain one mechanism of how obesity can cause deregulation in insulin resistance?
Pro-inflammatory cytokines, saturated FFAs, amino acids can activate Serine/Threonine kinases
Serine/Threonine kinases can phosphorylate IRS, reducing its Tyrosine phosphorylation and also increasing its degradation
Explain one mechanism of how obesity can cause deregulation in insulin resistance?
Pro-inflammatory cytokines, saturated FFAs, amino acids can activate Serine/Threonine kinases
Serine/Threonine kinases can phosphorylate IRS, reducing its Tyrosine phosphorylation and also increasing its degradation
When insulin binds, the cascade starts and IRS goes to the receptor but, because now IRS is phosphorylated on these amino acids, it cannot be phosphorylated by the receptor
The cascade stops so the message does not reach GLUT4 and the excess of glucose is not removed even if insulin is there
Insuline receptor:
PI3K can only bind to IRS when IRS is phosphorylated on WHAT? [1]
PI3K can only bind to IRS when IRS is phosphorylated on Tyrosines
How can insulin deficiency or resistance cause hyperglycaemia?
What happens at same time in diabetes patients with glucagon?
Only insulin alerts the peripheral tissues of blood glucose levels: so without insulin the body thinks it is in a fasting state, so releases more glucose. But only insulin causes decrease of glucose so get bad cycle occuring (even if doesnt need to)
Concurrently:
Excessive circulating glucagon levels (hyperglucagonaemia) have been reported in all forms of diabetes
What physiological responses occur in response to insuline resistance in obesity or pregnancy? [3]
What does this mean physiologically? [1]
New β cells can be generated in response to insulin resistance associated with obesity or pregnancy
Islets increase in both size and number due to Beta cell increase in size and number
Increased β function
THEREFORE Glucose tolerance can be maintained by increased insulin secretion
Which Ptx population are you most likely to see hypoglycaemia in? [1]
Which other populations may you see it in? [3]
Most likely in: diabetes patients
Also in:
* Some critical illnesses (end stage liver disease, sepsis, renal failure)
* Some counter-regulatory hormones deficiencies
* Insulin overproduction (insulinoma, nesidioblastosis)
Why may hypoglycaemia occur in diabetic ptx? [4]
Medications:
* Common complication when using insulin or other insulin secretagogues
* Skipped/postponed meals when taking medications
* Increasing physical activity without adjusting food ingestion/medications
Alcohol excess:
Inhibition of gluconeogenesis
What is an important symptom of mild hypoglycaemia?
Why is recurrent hypoglycaemia dangerous?
Mild hypoglycaemia:
* can lead to several hours of mental and physical recovery and can impact work performance
* can contribute to worry and fear, potentially leading to poor glycaemic control
Recurrent hypoglycaemia can lead to:
* suppression of the normal physiological counter-regulatory response
* development of impaired awareness of hypoglycaemia
What does severe hypoglycaemia look like?
Severe hypoglycaemia requires assistance from another person It is a diabetic emergency
- motor vehicle crashes
- seizures
- cardiac arrhythmias
- coma
- death
What does severe hypoglycaemia look like?
Severe hypoglycaemia requires assistance from another person It is a diabetic emergency
- motor vehicle crashes
- seizures
- cardiac arrhythmias
- coma
- death
How does impaired awareness of hypoglycaemia lead to more hypoglycaemia?
It is a progressive reduction of symptomatic and behavioural responses to hypoglycaemia
It is thought to develop as a consequence of whole-body adaptations to repeated insulin-induced hypoglycaemia and impaired counter-regulatory response
Which pathways are activated during hyperglycaemia that can cause damage [3]
- Oxidative stress: get increased expression and activity of vascular NADH oxidase. Leads to ROS accumulation
- Increase in polyol pathway: increased AGE production
- Converted to PKC pathway: creates more ROS
How can oxidative stress induce cellular damage? [3]
- Oxidative damage to macromolecules
- Impairment of NO signalling pathway
- Activation of pro-inflammatory signalling cascades
How can oxidative stress induce cellular damage? [3]
- Oxidative damage to macromolecules
- Impairment of NO signalling pathway
- Activation of pro-inflammatory signalling cascades
What are AGE products?
Advanced Glycation End products (AGEs) are proteins or lipids that become glycated
Causes:
Structural modificaiton of proteins: basement membrane thickness, reduced vascular elasticity etc
Interaction with AGE receptors: activation of signalling, gene expression, secretion of pro-inflammatory molecules, increased production of free radicals etc)
