L22 last slides DKA and some K+

Question 1

What % of B cells must be lost for young children with type 1 diabetes to present with hyperglycaemia compared to adults

What happens after first treatment with insulin

Answer 1

90% in kids.
Slower in older children, adults: 80-90% loss.

After first treatment: honeymoon phase of reduced 2’ effects: 0-2yrs because can make insulin.

Question 2

What are the 5 processes that insulin activates and inhibits

Answer 2

Activates:

1. glucose uptake in muscle + adipose:
   - inhibits Gluconeogenesis

2.Glycolysis: make ATP

3. Glycogen synthesis (storage in muscle, liver)
   - inhibits Glycogenolysis
4. Protein synthesis :
   - Inhibits Proteolysis

5.Uptake of ions (K+, Pi)

Inhibits:

3. Lipolysis (instead makes fatty acids)
4. Ketogenesis

Question 3

What are 4 counter-regulatory hormones to insulin and what is the main action

Answer 3

To increase blood sugar:

• Glucagon
• Catelcholamines (adrenaline)
• Cortisol (causes gluconeogenesis and proteolysis)
• Growth hormone (increase glucose under acute hypoglycaemia)

Question 4

What is the half life of insulin and how does this effect blood sugar levels throughout the day.
When is glycogen levels high in relation to insulin

Answer 4

1 minute half live so insulin levels fluctuate. thus not able to maintain steady blood sugar (only maintain range). This allows a gradient for uptake of glucose into cells.

Glycogen is made all the time but levels are highest when insulin low (in between meals and nighttime)

Question 5

Why is it better to have Glut4 transporters brought to the membrane triggered by insulin, rather than all the time.

Answer 5

GLUT4 is a passive transporter which allows glucose to follow its conc gradient. If stayed all the time glucose would leak back out of cell so needs removal.

Question 6

Where does the glucose in hyperglycaemia in diabetics come from (eg. what processes to make hyperglycaemia)

Answer 6

• 50% of glucose comes from reduced intake into cells

Lack of insulin simulates ‘starvation’- also removes inhibition on other factors.

• 50% comes from gluconeogenesis

1. Glucagon levels rise:
   increase in proteolysis and lipolysis
2. In liver: amino acids, glycerol and increased glycogenolysis are used for gluconeogenesis
3. Adrenaline release in between meals, induces gluconeogenesis in kidney also

Question 7

How are ketones made

- 3 substrates: lack of insulin, stress, and fat

Answer 7

1. Lack of insulin stimulates lipolysis in adipose tissue
   –> increased FFA which go to liver
   +
2. Excess Glucagon, (corticosteroids, catecholamine(STRESS), GH) stimulate activation of carnitine Acytltransferase and stimulate B oxidation.
3. Leads to accelerated ketogenesis: In mitochondria FFA –> acetyl CoA –> 2 steps
   - -> Acetoacetate which has 1:1 steady state conversion to
   a) B- hydroxybutyrate, b) some converted to acetone

Question 8

How does formation of acetoacetate lead to DKA

Answer 8

1. B- hydroxybutryic acid and acetoacetic acid dissociate completely.
2. Excess H+ leaves the liver and is buffered by bicarbonate in blood, leading to decrease in bicarb
3. Ketone bodies circulate as anions: increase anion gap (metabolic acidosis)

The decrease in HCO3 approximates the increase in anion gap in DKA due to hydroxy butyric acid and acetoacetic acid.

Question 9

What is the anion gap and the formula for it

Answer 9

Anion gap = Na+ – (Cl- + HCO3-)

If anion gap increases then indicative of metabolic acidosis : presence of unmeasured anions.

Question 10

What happens to Na and Cl balance in DKA. and what changes after treatment with volume replacement 0.9% NaCl. What is the other treatment to get plasma BOHB to fall

Answer 10

B- hydroxybutyrate is dissociated

• H+ –> Co2 and H2O (excreted and breathed off)
• B-hydroxybutyrate joins with Na from NaCl to make a salt which is excreted in urine

Therefore short term loss of Na but no loss of Cl in ECF
so after treatment:
we get normal Na but hyperchloraemia.
Other treatment is insulin to get BOHB to fall

Question 11

What ketones do urine ketone strips test for and is this a good test - what should we use

Answer 11

• Detect acetoacetate using Na nitroprusside and acetone if reagent also has glycine.
• Doesn’t detect b- hydroxybutyrate.
  Normally the ratio of BOHB: AcAc is 1:1 but in acidosis, BOHB can be 1.3-5.5 x higher so only detecting urine AcAc concentration can underestimate severity of ketonemia.

Therefore PoC devises for BoHB better

Question 12

What is the criteria to diagnose DKA

Answer 12

1. Hyperglycaemia: >11mmol
2. Venous pH <7.3 or bicarb <15 mmol
3. Presence of ketonemia or ketonuria - it is suggested that this be replaced by serum BOHB

Question 13

What feedback or feedforward systems are involved in K+ control - what does this mean

Answer 13

• Feedforward: anticipatory before serum K+ goes up,
  1. consumption of glucose or aminoacid meal stimulates Insulin release

2. protein rich meal increases glucagon + cAMP, which increases transtubular K+ gradient increasing GFR and 2x K excretion

• Feedback: increased K+ is the trigger itself and the system overshoots (backup)
  1. Aldosterone: increases uptake and excretion,

Question 14

What are 4 factors which can increase ECF [K+] and 1.5 that increase ICF K+

Answer 14

• Exercise causes K+ release into ECF (-but B adrenergic stimulation shift K+ into ICF )
• Increase in ECF osmolarity gets water out of cells, increasing ICF and ECF K+
• Acidosis increases ECF K+ (Loss from cells)
• Cell lysis increases ECF K+