Early onset (usually before age 25) of non-insulin dependent diabetes
Aetiology
- Single gene mutation (monogenetic) which is dominantly affected and predominantly affects β-cell function
- Most common form of monogenetic diabetes
Pathophysiology
- Common clinical features to both type 1 and type 2 diabetes
- Genetic defective glucose sensing in the pancreas and/or loss of insulin secretion
- At least 150 different mutations (6 genes) have been identified
- 3 types of mutation:
- Glucokinase (14%)
- Transcription factors (75%)
- MODY X (11%)
Glucokinase mutations
- 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
Transcription factor mutations
- 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.
MODY X
Clinical presentation
Glucokinase mutations
Transcription factor mutations
- Progressive hyperglycaemia
Investigations
Oral glucose tolerance test
- 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
Management
Glucokinase mutations
- Not associated with an increased risk of microvascular disease and can be managed with diet alone
Transcription factor mutations
- 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
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