Ketoacidosis

Question 1

Pathogenesis of T1DM

Answer 1

AKA insulin-dependent DM, caused by lack of insulin. Beta cells in pancreatic islets are gradually destroyed (autoimmune) and patients become dependent on insulin administration for survival -> severe symptoms if untreated.

Question 2

Why do we get diabetic complications even though glucose is still present?

Answer 2

1. No insulin means the body believes there is no glucose, glucagon released
2. Starvation procedures started by mobilising gluconeogenesis substrates from muscle and fat
3. System gets ++ glucose and FFAs

Question 3

How does insulin deficiency increase glucose synthesis in the liver?

Answer 3

Increases both gluconeogenesis (lactate, AAs and glycerol) and glycogenolysis (decreases glycogen synthase and increases glycogen phosphorylase): glucagon stimulates these

Question 4

How does insulin deficiency impair peripheral glucose uptake?

Answer 4

GLUT4-mediated glucose uptake in adipose and muscle is insulin dependent so without insulin we can’t absorb glucose.
Some other transporters (GLUT3 in brain and GLUT1 for basal cell function) still work but are insufficient.

Question 5

Why can’t we convert excess BGL to energy stores via glycogen?

Answer 5

A. Glucose doesn’t enter muscle/adipose cells
B. Decreased activity of glycogen synthase decreases glycogen synthesis
C. Decreased storage of glucose into TGs in adipose tissue (impaired GLUT4)

Question 6

Does insulin deficiency increase or decrease LPL and what is the effect of this?

Answer 6

DECREASES

Chylomicrons and VLDL aren’t properly cleared so high TGs, causing mild-moderate hypertryglyceridaemia

Question 7

Does insulin deficiency increase or decrease HSL and what is the effect of this?

Answer 7

INCREASES
Inhibition of HSL is decreased. As its levels increase, lipolysis increases and FFas are released from adipose tissue.
Glycerol used for gluconeogenesis in liver
FFAs undergo beta-oxidation for ketogenesis

Question 8

What happens to hepatic VLDL in this process? (compare to what should normally happen)

Answer 8

Normal: insulin decreases ApoB100 and VLDL production
When insulin decreases, TAG levels rise due to increased FFAs and increased ApoB100 production promotes the secretion of VLDLS

Question 9

In a complete lack of insulin, do we get ketones?

Answer 9

Yes! HSL is completely non-suppressed so we get excess FFAs and excess acetyl-CoA. These products can’t enter TCA so are used for ketone synthesis instead which can lead to diabetic ketoacidosis

Question 10

When does ketogenesis occur in normal function?

Answer 10

After several days of prolonged fasting. Promoted by glucagon, made in liver.
Used in periphery as fuel instead of glucose (liver can’t use ketones).

Question 11

What are the 3 main ketone bodies?

Answer 11

Acetoacetate
Acetone
D-beta-hydroxybutyrate

Question 12

Why can’t acetyl CoA enter TCA cycle?

Answer 12

Oxaloacetate in TCA is taken out for gluconeogenesis so can’t combine with Acetyl-CoA to form citrate (next step)
This is why Acetyl-CoA undergoes beta-oxidation instead.

Question 13

How does insulin deficiency increase proteolysis in muscle?

Answer 13

Decreases AA uptake and protein synthesis and increases protein degradation to release AAs for gluconeogenesis
(some AAs also are ketogenic eg. leucine and lysine)

Question 14

Why do T1DM patients get kidney issues?

Answer 14

As BGL rises more is filtered by the kidneys (resorption threshold 10nM) so we get glycosuria.
The excess glucose causes osmotic diuresis to the lumen and hence frequent urination and dehydration result.

Question 15

What is a hyperglycaemic hyperosmolar state?

Answer 15

High BSL consequence seen in T1 and T2DM patients (T2 more)
Blood becomes ++ concentrated due to increases diuresis and causes drowsiness.
Treat: insulin and lots of fluids

Question 16

S&S of diabetic ketoacidosis?

Answer 16

Thirst and urination
Weakness/fatigue
Confusion, apathy, drowsiness
Kussmaul respiration
Nausea, vomiting and stomach pain
Fruity breath

Question 17

What is ketoacidosis? (also what are ketonemia and ketonuria)

Answer 17

Metabolic acidosis from abnormal accumulation of ketone bodies.
Ketonemia is rise in blood
Ketonuria is rise in urine (acetoacetate urine test)

Question 18

Why do we get DKA S&S?

Answer 18

Nausea and vomiting due to acidosis

Kussmaul respiration in an attempt for respiratory compensation

Question 19

What are the electrolyte inbalances in DKA?

Answer 19

Decreased K, Na, Pi and bicarb. Increased by osmotic diuresis, dehydration, maybe vomiting, serum hyperosmmolarity, metabolic acidosis.
K loss is the most characteristic.

Question 20

How is K lost and how do we treat?

Answer 20

Lost as above but also due to K/H exchange, moving it to the ECF for acidosis (then lost in urine)
Initially serum K is elevated due to the transfer and similarly usually falls in treatment as insulin therapy drives K into cells (need to monitor so life-threatening hypokalemia may develop!)