Flashcards in Lecture 18 - Clinical endocrinology Deck (30):
What is a sign of diabetes?
Why is extreme wasting a sign of diabetes?
When we have no insulin being produced (like in T1DM), there is nothing to push glucose into the cells (hence why there is an increase in glucose in the blood). Because of this there is no energy into the cells and it causes a state of starvation.
What is the pathology in type 1 diabetes?
Typically it is an autoimmune disorder.
1. Infiltration of white blood cells (may be T helper 17 cells).
2. Overtime the WBC infiltrate the entire islet, thus the beta islet cells are destroyed and are unable to produce insulin. Basically there is an increase in antibodies.
3. There is a stage where there are enough beta cells to produce enough insulin, thus there is no hyperglycaemia = honeymoon phase.
4. Eventually the remaining beta cells cannot compensate, so hyperglycaemia occurs.
What does insulin do?
Binds to insulin receptor on cells and does the following:
1. Translocation of GLUT4 transporter to allow for the influx of glucose into the cells.
2. Glycogen synthesis - forms glucose into glycogen so that it can be stored and released when sugar levels are low. Basically another way to decrease glucose levels.
3. Glycolysis - breaks down glucose.
4. Fatty acid synthesis.
Describe the process of fatty acid synthesis?
When there is prolongation of decreased insulin levels (in diabetes mellitus) the following occurs:
1. Adipose tissue is broken down into triglycerides and NEFA and glycerol (all done by enzyme lipase which is inhibited by insulin - thus a higher level of insulin means no breakdown of FA).
2. NEFA is turned into FA in the liver (stored in the hepatocyte).
3. FA can undergo beta-oxidation and either go into the Krebs cycle or become ketones.
What happens to FA in the liver in a normal person?
FA undergo beta-oxidation to become acetyl-coa, where they can enter the Krebs cycle or become ketones. Most likely they enter the krebs cycle.
What happens to FA in the liver in a diabetic person?
FA undergo beta-oxidation to become acetyl-coa, where they become ketones. They can't go into the krebs cycle because there is an increase in gluconeogenesis depleting oxaloacetate (substrate in the krebs cycle). Basically there are not enough substrates (due to starvation at the start) to be involved in the krebs cycle. Thus FA have to become ketones.
What happens to the ketones once they leave the liver?
Ketones become beta-hydroxybutyric acid and acetoacetic acid.
N.B. Ketones can be used for great brain energy.
What happens with the beta-hydroxybutyric acid?
B-hydroxybutyric acid dissociates completley and gives off an H+. This H+ is buffered by circulating bicarbonate.
What happens in glucagon?
When there is not enough sugar, glucagon converts glycogen to glucose causing an increase in sugar.
Why does glucagon excess occur in diabetic ketoacidosis?
Because all the glycogen has been broken down as an energy store (due to not enough sugar in our cells as insulin is not pushing the glucose into our cells), there is excess glucagon.
What does glucagon excess do in diabetic ketoacidosis?
It causes there to be an increase in the liver carnitine and a decrease in malonyl-coa. This causes activation of carnitine acyltransferase. Which causes more ketones to be made.
What does stress do in diabetic ketoacidosis?
Stress produces counter-regulatory hormones that do the following:
1. Glycogenolysis - breakdown of glycogen to glucose-1-phosophate (this is because there is no insulin, so no glucose going into cells, so more glucose is made).
3. Lipolysis - this is above where ketone bodies are made from FFA.
What does lack of insulin do in diabetic ketoacidosis?
Due to there being no insulin (typically for a period of time - weeks to months) there is an increase in glucose in the blood, because glucose is not being pushed into the cells. The cells don't get energy, so they try and get energy from any source, eventually they deplete all other sources so fat is broken down into FFA. In the liver FFA undergoes beta-oxidation where it is made into acetyl-coa. Due to the other sources being depleted (i.e. oxaloacetate - substrate in krebs cycle) acetyl-coa cannot go into the krebs cycle to create ATP, so it is made into ketones. Once as a ketone, it is made into beta-hydroxybutyric acid and acetoacetic acid.
What is needed in diabetic ketoacidosis?
1. Lack of insulin.
3. Glucagon excess.
Why is there an anion gap with DKA?
Because BHB (beta-hydroxybutyric acid) are anions they increase the anion gap. This is because they replace the bicarbonate that is lost.
Why is there increased chloride in DKA?
BHB gives off an H+ (basically H+ is lost), so it is negatively charged so it needs to become in equilibrium so it gets a sodium (Na+) from NaCl. This creates BHB-Na which is excreted in urine. This means that there is excess chloride ions.
Why is there metabolic acidosis in DKA?
BHB dissociates an H+ ion, which needs to be buffered in equilibrium so it goes the opposite way so there is a decrease in HCO3- (bicarbonate).
What is the current criteria for DKA?
1. Blood glucose > 11mmol/L (hyperglycaemia).
2. Venous pH <7.3 (acidosis) or HCO3- <15mmol/L.
3. Ketonemia or ketouria (ketones in blood vs urine.
What is the suggested criteria for DKA?
1. Blood glucose >11mmol/L.
2. Venous pH <7.3.
3. Serum BHB >3mmol/L.
What is the potassium like in ECF(blood) and ICF(cells)?
Majority of K+ is in our cells (98% - 3300mEq) and only 2% (70mEq) in our serum/blood.
What happens when we eat a meal?
Typically in a meal there is a lot of potassium in that meal, which means if not treated to straight away there is an increase in serum potassium to levels such as 9.2mmol/L (normal = 3.5-5mmol/L). This is bad as it can cause cardiac arrest. So our body has a feedforward mechanism and feedback mechanism to excrete the potassium that we eat.
What is significant about the feedforward mechanism and not about the feedback mechanism?
The feedback mechanism is slow and takes too long to respond to high serum levels of K+, thus too long so cardiac arrests can occur. The feedforward mechanism is fast and anticipatory so we can get rid of K+ without waiting for the serum levels of it.
What does the feedforward mechanism do?
There are sensors in the gut which sense potassium and it sends signal to the kidney to excrete potassium. Overall this enhances excretion. This is mainly done via insulin - there is an increase in the Na/K/ATPase channel, which increases K+ uptake into the cells.
Is insulin dependent to potassium?
Insulin is independent to potassium. So the amount of potassium that we eat does not affect the amount of insulin released.
What does the feedback mechanism do?
There is an increase in aldosterone secreted. Aldosterone stimulates Na/K/ATPase channels which causes an increase of potassium uptake via cells. It also inserts potassium channel of apical membrane in principal cells which causes more potassium to be excreted from the kidneys. Overall this decreases serum potassium.
What else does the feedback mechanism do?
Beta-2 stimulation which causes potassium to shift from the serum to cells (decrease serum K+).
What happens to potassium levels with acidosis?
There is a decrease in potassium in the cells because H+ is taken up by the cells, so ECF (serum) has a apparent low K+ level so K+ is kicked out of the cells into the blood. This causes an increase in serum potassium.
This may also be due to acidosis inhibiting Na/K/ATPase channel.
What happens to potassium levels with beta blockers?
Beta blockers stop beta-2 activation, so there is an increase in potassium in the serum as it can't be taken up by the cells. That is why you have to be careful with patients on beta-blockers and watch their potassium levels.