MODY – Monogenic Diabetes – the basics

Question 1

MODY (3)

Answer 1

Autosomal dominant inheritance

Non-insulin dependent diabetes

Age of onset usually before age 25

Question 2

Types of monogenic diabetes (4)

Answer 2

Defects in insulin secretion=

MODY – Maturity Onset Diabetes of the Young
~11 genes identified as causal
Neonatal Diabetes-Many genes – 35 - can explain up to 82% of Neonatal diabetes

Defects in insulin action=

9 genes – defects in insulin signalling pathway (e.g. AKT, INSR) or fat storage (e.g. CIDEC)

Question 3

Glucokinase mutations (4)

Answer 3

if glucokinase found in patient, insulin treatment not needed!

• Glucokinase activity impaired,resulting in a glucose sensing defect - blood glucose threshold for insulin secretion is increased
• Everything else about the β-cell is normal
• They might have higher fasting glucose from birth - stable, doesnt require treatment, not associated with complications

Question 4

Transcription factor mutations (3)

Answer 4

• The main transcription factor mutations are HNF-1⍺, HNF-1β, HNF-4⍺
• Play key roles in pancreas foetal development and neogenesis
• Also regulate β-cell differentiation and function - glycolytic flux, expresion of GLUT2 transports, insulin secretion etc

Question 5

Glucokinase mutations presentation (2)

Answer 5

-Onset at birth
- Stable hyperglycaemia

Question 6

Transcription factor mutations presentation (2)

Answer 6

• Adolescence/YA onset
• Progressive hyperglycaemia

Question 7

Investigations (2)

Answer 7

Oral glucose tolerance test (OGTT)

• Patients with a glucokinase mutation will have a high fasting blood glucose (~7 mmol) but bring their glucose down very well when given oral challenge
• Patients with a transcription factor mutation will have a normal fasting blood glucose but DON’T respond well to glucose challenge

Genetic screening

• Can be used to confirm type of mutation

Question 8

Management- Glucokinase mutations

Answer 8

• Not associated with an increased risk of microvascular disease and can be managed with diet alone

Question 9

Management- Transcription factor mutations (4)

Answer 9

• Diet + treatment with insulin or sulphonylureas
  
  • Respond very well to sulphonylureas (~4 x more sensitive than patients with T2DM) as MODY patients usually have β-cell function available
  • Patients previously misdiagnosed as T1DM who are on insulin can safely switch to low dose SUs
• Complications frequent