Lecture 4 - Monogenic Diabetes

Question 1

What symptoms are indicators that a patient has MODY?

Answer 1

Early of of onset
Patients can take insulin holidays (non-insulin dependent)
Autosomal dominant inheritance pattern seen in family pedigree
Not related to obesity
General symptoms of diabetes (hyperglycaemia, increased thirst and urination)

Question 2

What are the 4 most commonly mutated genes associated with MODY, and what is the function of each?

Answer 2

Glucokinase
HNF1-alpha
HNF4-alpha
HNF1-beta

Question 3

Describe the processes that lead to insulin release in a healthy person

Answer 3

1. Glucose uptake into beta cell by GLUT2
2. GCK metabolises glucose into glucose-6-phosphate
3. Increased ATP
4. ATP-dependent K+ channels close
5. Beta cell depolarisation
6. VOCCs open
7. Vesicles containing insulin fuse with membrane

Question 4

Why is MODY often mistaken for Type 1 diabetes?

Answer 4

1. Both not associated with obesity
2. Both typically diagnosed at young age
3. Both have at least a partial genetic component so might run in families

Question 5

What is a difference between MODY and Type 1 diabetes?

Answer 5

MODY is non always insulin dependent where as Type 1 is insulin dependent
MODY patients can take insulin ‘holidays’ and not die

Question 6

What is HbA1c?

Answer 6

A patient’s average blood glucose over the past 3 months

Question 7

What is the cause of Type 2 diabetes?

Answer 7

Related to lifestyle/obesity

Reduced sensitivity to insulin so glucose not absorbed, leading to hyperglycaemia

Question 8

What is the main treatment for Type 2 diabetes and how does it work?

Answer 8

Metformin

Prevents the liver from producing glucose and increases insulin sensitivity

Question 9

What is neonatal diabetes?

Answer 9

A form of monogenic diabetes

Diagnoses in babies under 6 months

Question 10

What is the cause of neonatal diabetes and what treatment is recommended?

Answer 10

Mostly caused by mutations in the ATP-sensitive potassium channels
Treated with sulfonylureas

Question 11

What is DEND?

Answer 11

Developmental delay, Epilepsy and Neonatal Diabetes
Some cases of neonatal diabetes also result in neurological symptoms as the mutated potassium channel is also found in the brain

Question 12

What are the two main benefits of diagnosing MODY?

Answer 12

Can potentially switch treatment to sulfonylureas

Can correctly diagnose other family members too

Question 13

What is the function of GCK and what treatment is recommended for MODY sufferers with a GCK mutation?

Answer 13

Glucokinase
Pancreatic glucose sensor
If mutated, glucose won’t be sensed and insulin won’t be released
Treated with sulfonylureas

Question 14

What is the function of HNF1-alpha and what treatment is recommended for MODY sufferers with a HNF1-alpha mutation?

Answer 14

Transcription factor involved in beta cell gene transcription
If mutated, beta cells are defective as glucose won’t be sensed and insulin won’t be released
Treated with sulfonylureas

Question 15

What is the function of HNF4-alpha and what treatment is recommended for MODY sufferers with a HNF4-alpha mutation?

Answer 15

Transcription factor involved in beta cell gene transcription
If mutated, beta cells are defective as glucose won’t be sensed and insulin won’t be released
Treated with sulfonylureas

Question 16

What is the function of HNF1-beta and what treatment is recommended for MODY sufferers with a HNF1-beta mutation?

Answer 16

Transcription factor involved in beta cell development
If mutated, there will be an insufficient number of beta cells to produce insulin
Treated with insulin

Question 17

How does sulfonylureas treatment work?

Answer 17

Closes the ATP-sensitive potassium channels on beta cells, allowing depolarisation, activation of VOCCs and release of insulin